FGFR3 inhibitor compounds

ABSTRACT

The present invention provides compounds of the formula: 
                         
for use in the treatment of systemic sclerosis, fibrosis (e.g. pulmonary fibrosis), achondroplasia, thanatophoric dysplasia (e.g. type I), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer.

BACKGROUND

Fibroblast growth factor (FGF) has been recognized as an important mediator of many physiological processes, such as morphogenesis during development, fibrosis, and angiogenesis. The fibroblast growth factor receptor (FGFR) family consists of five members four of which (FGFR 1-4) are glycoproteins composed of extracellular immunoglobulin (Ig)-like domains, a hydrophobic transmembrane region and a cytoplasmic part containing a tyrosine kinase domain. FGF binding leads to FGFR dimerization, followed by receptor autophosphorylation and activation of downstream signaling pathways. Receptor activation is sufficient for the recruitment and activation of specific downstream signaling partners that participate in the regulation of diverse processes such as cell growth, cell metabolism and cell survival. Thus, the FGF/FGFR signaling pathway has pleiotropic effects on many biological processes critical to tumor cell proliferation, migration, invasion, and angiogenesis.

SUMMARY

Provided herein are compounds of the formula:

or a pharmaceutically acceptable salt thereof, wherein A, X₁, X₂, X₃, X₄, Y, Y₁, Y₂, Y₃, Y₄, Z, Z₁, R² and R⁶ are as defined herein.

Provided herein are compounds of the formula:

or a pharmaceutically acceptable salt thereof, wherein A, X₁, X₂, Y, Y₁, Y₂, Z, Z₁, R², R³, R⁴, R⁵, R⁶ and R⁹ are as defined herein.

Provided herein are compounds of the formula:

or a pharmaceutically acceptable salt thereof, wherein A, X₁, X₂, Y, Y₁, Y₂, Z′, R², R³, R⁴, R⁵ and R⁶ are as defined herein.

Provided herein are pharmaceutical compositions comprising a compound of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.

Provided herein are methods of using the compounds of formula (I), (II), (IA) or (III), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof, to treat systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or proliferative disorders such as cancer, particularly to treat FGFR3-associated cancer. The methods include administering an effective amount of a compound of formula (I), (II), (IA) or (III), or a pharmaceutically acceptable salt thereof, to a patient in need.

DESCRIPTION

Provided herein are compounds believed to have clinical use for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome, proliferative disorders such as cancer and particularly for the treatment of FGFR3-associated cancer.

Certain compounds provided herein have superior FGFR3 potency compared to certain previously known FGFR inhibitors. Certain compounds provided herein have superior selectivity for FGFR3 over FGFR1 compared to certain previously known FGFR inhibitors, reducing potential dose limiting toxicity caused by inhibition of FGFR1 (e.g. hyperphosphatemia).

The compounds provided herein are of formula:

wherein

-   -   A is pyrazole, triazole, thiadiazole or oxadiazole, substituted         with R¹ and R^(1A);     -   R¹ is hydrogen or C₁-C₃ alkyl;     -   R^(1A) is hydrogen, halo, CN, or C₁-C₃ alkyl optionally         substituted with one or more substituents independently selected         from halo, OH, and OCH₃;     -   X₁ and X₂ are independently selected from N and C, wherein when         one of X₁ or X₂ is N the other is C;     -   X₃ is N or CH;     -   X₄ is N or C—R⁹;     -   Y is NH, O, S or a bond;     -   Y₁ is a bond, CHR⁷, CH₂—CHR⁷, CHR⁷—CH₂, CF₂, CH₂—CF₂ or CF₂—CH₂;     -   Y₂ is a bond, CHR³, CH₂—CHR³, CHR³—CH₂, CF₂, CH₂—CF₂ or CF₂—CH₂;     -   Y₃ is CR⁴R⁵ or CF₂;     -   Y₄ is CR³R⁴, or CF₂;     -   Z is a bond, CHR^(9A), CR⁴R^(4A), CR⁴R^(4A)—CH₂, CH₂—CR⁴R^(4A),         cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane,         bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine;     -   Z₁ is a bond when Z is a bond, CR⁴R^(4A), CR⁴R^(4A)—CH₂,         CH₂—CR⁴R^(4A), cyclobutyl, cyclopentyl, cyclohexyl,         bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine,         pyrrolidine or piperidine, or Z₁ is CH₂ or CH₂—CH₂ when Z is         CHR^(9A);     -   Z₂ is a bond, C(O), SO₂ or —NR⁴C(O);     -   Z₃ is a bond, C(O), SO₂ or —NR⁴C(O);     -   R² is C₁-C₅ alkyl or R⁸, wherein C₁-C₅ alkyl is optionally         substituted with one or more substituents independently selected         from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl,         —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alky and C₃-C₅ cycloalkyl are         optionally substituted with one or more substituents         independently selected from halo, OH, OCH₃, methylamine,         N,N-dimethylamine and CN;     -   R³ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl, cyclopropyl, or one R³         is fused with R⁵ or R⁷ to form CH₂, CH₂—CH₂ or CH₂OCH₂;     -   R⁴ is hydrogen or C₁-C₃ alkyl;     -   R^(4A) is hydrogen, halo, OH, or C₁-C₃ alkyl;     -   R⁵ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl, cyclopropyl, or is         fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂;     -   R⁶ is hydrogen, halo, C₁-C₅ alkyl, CN, 3-6 membered cycloalkyl,         4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered         heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered         heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl         are optionally substituted with one or more substituents         independently selected from halo, methyl, halomethyl, OH or OCH₃         and wherein C₁-C₅ alkyl is optionally substituted with one or         more substituents independently selected from halo, OH and OCH₃;     -   R⁷ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl or is fused with one R³         to form CH₂, CH₂—CH₂ or CH₂OCH₂;     -   R⁷ is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl,         5-6 membered aryl or 5-6 membered heteroaryl, optionally fused         or substituted with R^(8A);     -   R^(8A) is 3-6 membered cycloalkyl, 4-6 membered         heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;     -   R⁹ is hydrogen, C₁-C₃ alkyl, or is fused with R^(9A) to form CH₂         or CH₂—CH₂;     -   R¹⁰ is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl,         5-6 membered aryl or 5-6 membered heteroaryl, optionally fused         or substituted with R^(8A);     -   R₁₁ is C₁-C₄ alkyl, NH₂, NHC₁-C₃ alkyl, NHC₃-C₅ cycloalkyl or         N(C₁-C₃ alkyl)₂, wherein C₁-C₄ alkyl, C₁-C₃ alkyl and C₃-C₅         cycloalkyl are optionally substituted with one or more         substituents independently selected from halo, OH, OCH₃,         methylamine, N,N-dimethylamine and CN;     -   R¹² is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, NH₂, NHC₁-C₃ alkyl,         NHC₃-C₅ cycloalkyl or N(C₁-C₃ alkyl)₂, wherein C₁-C₄ alky, C₁-C₃         alkyl and C₃-C₅ cycloalkyl are optionally substituted with one         or more substituents independently selected from halo, OH, OCH₃,         methylamine, N,N-dimethylamine and CN; and     -   R⁸, R¹⁰ and R^(8A) are optionally substituted with one or more         substituents independently selected from halo, OH, CN, —OC₁-C₄         alkyl, —OC₃-C₅ cycloalkyl and —Z₃—R¹² wherein C₁-C₄ alky and         C₃-C₅ cycloalkyl are optionally substituted with one or more         substituents independently selected from halo, OH, OCH₃,         methylamine, N,N-dimethylamine and CN;     -   or a pharmaceutically acceptable salt thereof, and of formula:

-   -   or a pharmaceutically acceptable salt thereof, and of formula:

-   -   or a pharmaceutically acceptable salt thereof. In formula (II),     -   X₁ and X₂ are independently selected from N and C, wherein when         one of X₁ or X₂ is N the other is C;     -   Z is a bond, CHR^(9A), azetidine, pyrrolidine or piperidine;     -   Z₁ is a bond when Z is a bond, azetidine, pyrrolidine or         piperidine, or Z₁ is CH₂ or CH₂—CH₂ when Z is CHR^(9A); and     -   R⁹ is hydrogen or is fused with R^(9A) to form CH₂ or CH₂—CH₂.

In formula (III),

X₁ and X₂ are independently selected from N and C, wherein when one of X₁ or X₂ is N the other is C; and

Z′ is a bond, azetidine, pyrrolidine or piperidine.

In formula (II) and (III),

A is pyrazole, triazole, thiadiazole or oxadiazole, optionally substituted with R¹;

R¹ is C₁-C₃ alkyl;

Y is NH, O, or a bond;

Y₁ is a bond, CHR⁷, CH₂—CHR⁷ or CHR⁷—CH₂;

Y₂ is a bond, CH₂, CF₂, CHR³, CH₂—CHR³ or CHR³—CH₂;

R² is C₁-C₅ alkyl or R⁸, wherein C₁-C₅ alkyl is optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R¹⁰;

R³ is hydrogen, C₁-C₃ alkyl, or one R³ is fused with R⁵ or R⁷ to form CH₂ or CH₂—CH₂;

R⁴ is hydrogen, or C₁-C₃ alkyl;

R⁵ is hydrogen, or is fused with one R³ to form CH₂ or CH₂—CH₂;

R⁶ is hydrogen, CH₃, CN, Cl or F;

R⁷ is hydrogen, or is fused with one R³ to form CH₂ or CH₂—CH₂;

R⁷ is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused with R^(8A);

R^(8A) is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;

R¹⁰ is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A); and

R⁸, R¹⁰ and R^(8A) are optionally substituted with one or more substituents independently selected from halogen, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)₂CH₃, C(O)NH₂, N,N-dimethylamine and C(O)N,N-dimethylamine.

In the compounds of formula (I), (II) or (III), X₁ can be C, and X₂ can be N; or X₁ can be N, and X₂ can be C.

In the compounds of formula (I), (II) or (III), X₁ can be C, and X₂ can be N, forming:

wherein * indicates the connection point to A in formula (I), (II) or (III).

In the compounds of formula (I), (II) or (III), X₁ can be N, and X₂ can be C, forming:

wherein * indicates the connection point to A in formula (II. (III or (III).

The specific chemical naming conventions used herein are intended to be familiar to one of skill in the chemical arts. Some terms are defined specifically for additional clarity.

As used herein, the term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, the term “C₁-C₅ alkyl” as used herein refers to saturated linear or branched-chain monovalent hydrocarbon radicals of one, two, three, four or five carbon atoms. Examples of C₁-C₅ alkyl include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, and neopentyl. Examples of C₁-C₄ alkyl include, but are not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, and 2-methyl-2-propyl. Examples of C₁-C₃ alkyl include, but are not limited to, methyl, ethyl, 1-propyl or isopropyl.

As used herein, the term “cycloalkyl” means a saturated cyclic hydrocarbon group containing the indicated number of carbon atoms. For example, the term “3-6 membered cycloalkyl” as used herein refers to a saturated cyclic hydrocarbon group having three, four, five or six carbon atoms. Examples of 3-6 membered cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “heterocycloalkyl” means a saturated cyclic group containing the indicated number of atoms selected from C(O)₀₋₁, N, O and S(O)₀₋₂. For example, the term “5-6 membered heterocycloalkyl” as used herein refers to a saturated cyclic ring system having five or six ring atoms, one, two or three of which are selected from N, O and S(O)₀₋₂, the remainder being C(O)₀₋₁. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl oxozolid-2-onyl and isothiazolid-2-onyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl oxozolid-2-onyl and isothiazolid-2-onyl.

As used herein, the term “aryl” refers to an aromatic cyclic hydrocarbon group having the indicated number of carbon atoms. For example, the term “5-6 membered aryl” as used herein refers to an aromatic cyclic hydrocarbon group having five or six carbon atoms. Examples of 5-6 membered aryls include cyclopentadienyl and phenyl.

As used herein, the term “heteroaryl” refers to an aromatic cyclic group having the indicated number of atoms selected from C, N, O and S. For example, the term “5-6 membered heteroaryl” as used herein refers to an aromatic cyclic group having five or six ring atoms, one, two or three of which are selected from N, O and S, the remainder being C. Examples of 5-6 membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl and thiadiazolyl. Examples of 6 membered heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

As used herein the term “halogen” or “halo” refers to F (fluoro), Cl (chloro), Br (bromo) and I (iodo).

As used herein the term “halomethyl” refers to —CH₃, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

As used herein the term “oxo” refers to the substitution of CH₂ with O to form C(O).

As used herein the term “N(C₁-C₃ alkyl)₂” allows the independent selection of each C₁-C₃ alkyl substituent, for example, N may be substituted by methyl and ethyl.

As used herein the substituent —NR⁴C(O) is connected to R² through N.

Also provided is a compound of the formula:

wherein

A is pyrazole, triazole, thiadiazole or oxadiazole, optionally substituted with R₁;

R¹ is C₁-C₃ alkyl;

X_(1A) and X_(2A) are independently selected from N and CH, wherein when one of X_(1A) or X_(2A) is N the other is CH;

Y is NH, O, or a bond;

Y₁ is a bond, CHR⁷, CH₂—CHR⁷ or CHR⁷—CH₂;

Y₂ is a bond, CH₂, CF₂, CHR³, CH₂—CHR³ or CHR³—CH₂;

Z is a bond, CHR^(9A), azetidine, pyrrolidine or piperidine;

Z₁ is a bond when Z is a bond, azetidine, pyrrolidine or piperidine, or Z₁ is CH₂ or CH₂—CH₂ when Z is CHR^(9A);

R² is C₁-C₅ alkyl or R⁸, wherein C₁-C₅ alkyl is optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R¹⁰;

R³ is hydrogen, C₁-C₃ alkyl, or one R³ is fused with R⁵ or R⁷ to form CH₂ or CH₂—CH₂;

R⁴ is hydrogen, or C₁-C₃ alkyl;

R⁵ is hydrogen, or is fused with one R³ to form CH₂ or CH₂—CH₂;

R⁶ is hydrogen, CH₃, CN, Cl or F;

R⁷ is hydrogen, or is fused with one R³ to form CH₂ or CH₂—CH₂;

R⁷ is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A);

R^(8A) is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;

R⁹ is hydrogen or is fused with R^(9A) to form CH₂ or CH₂—CH₂;

R¹⁰ is 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A); and

R⁸, R¹⁰ and R^(8A) are optionally substituted with one or more substituents independently selected from halogen, CN, methyl, halomethyl, methoxy, ethyl, ethoxy, methylamine, S(O)₂CH₃, C(O)NH₂, N,N-dimethylamine and C(O)N,N-dimethylamine;

or a pharmaceutically acceptable salt thereof.

In the compound of formula (IIA), X_(1A) can be CH, and X_(2A) can be N, forming:

wherein * indicates the connection point to A in formula (IIA), forming a compound of the formula:

In the compound of formula (IIA), X_(1A) can be N, and X_(2A) can be CH, forming:

wherein * indicates the connection point to A in formula (IIA), forming a compound of the formula:

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, 1,2,4 triazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, 1,2,5 thiadiazole, 1,3,4 thiadiazole, 1,2,3 oxadiazole, 1,2,4 oxadiazole, 1,2,5 oxadiazole, or 1,3,4 oxadiazole, substituted with R¹ and R^(1A).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is CH₃.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, 1,2,4 triazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, 1,2,5 thiadiazole, 1,3,4 thiadiazole, 1,2,3 oxadiazole, 1,2,4 oxadiazole, 1,2,5 oxadiazole, or 1,3,4 oxadiazole, optionally substituted with R¹.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, optionally substituted with R¹.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with CH₃.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); and R¹ can be C₁-C₃ alkyl.

In the compounds of formula (I), Z can be CHR^(9A), cyclobutyl, azetidine, pyrrolidine or piperidine.

In the compounds of formula (I), Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (II) or (IIA), Z can be CHR^(9A), azetidine, pyrrolidine or piperidine.

In the compounds of formula (II) or (IIA), Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (II) or (IIA).

In the compounds of formula (II) or (IIA), Z can be:

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (II) or (IIA).

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be selected from CH₂ or CH₂—CH₂, and R⁹ can be fused with R^(9A) to form CH₂ or CH₂—CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be CH₂, and R⁹ can be fused with R^(9A) to form CH₂ or CH₂—CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be CH₂—CH₂, and R⁹ can be fused with R^(9A) to form CH₂ or CH₂—CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be selected from CH₂ or CH₂—CH₂, and R⁹ can be fused with R^(9A) to form CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be selected from CH₂ or CH₂—CH₂, and R⁹ can be fused with R^(9A) to form CH₂—CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be CH₂, and R⁹ can be fused with R^(9A) to form CH₂.

In the compounds of formula (I), (II) or (IIA), Z can be CHR^(9A), Z₁ can be CH₂—CH₂, and R⁹ can be fused with R^(9A) to form CH₂—CH₂.

In the compounds of formula (III), Z′ can be:

wherein ** indicates the connection point to A and * indicates the other connection point from Z′ in formula (III).

In the compounds of formula (III), Z′ can be:

wherein ** indicates the connection point to A and * indicates the other connection point from Z′ in formula (III).

In the compounds of formula (I), (II) or (IIA), Z can be a bond.

In the compounds of formula (III), Z′ can be a bond.

In the compounds of formula (I), (II) or (IIA), Z₁ can be a bond.

In the compounds of formula (I), (II), (IIA) or (III), Y can be NH or O.

In the compounds of formula (I), (II), (IIA) or (III), Y can be O.

In the compounds of formula (I), Y₁ can be a bond, CHR⁷, CH₂—CHR⁷ or CHR⁷—CH₂, wherein R⁷ is selected from hydrogen, F, OH and CH₃; and Y₂ can a bond, CHR³, CH₂—CHR³ or CHR³—CH₂, wherein R³ is selected from hydrogen, F, OH and CH₃.

In the compounds of formula (I), Y₁ can be a bond or CHR⁷, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond or CHR³, wherein R³ is hydrogen, F, OH or CH₃.

In the compounds of formula (I), Y₁ can be a bond, CHR⁷, CH₂—CHR⁷ or CHR⁷—CH₂, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond, CHR³, CH₂—CHR³ or CHR³—CH₂, wherein R³ is hydrogen, F, OH or CH₃, forming:

wherein * indicates the connection point to Z₁ in formula (I).

In the compounds of formula (I), Y₁ can be a bond or CHR⁷, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond or CHR³, wherein R³ is hydrogen, F, OH or CH₃, forming:

wherein * indicates the connection point to Z₁ in formula (I).

In the compounds of formula (II), (IIA) or (III), Y₁ can be a bond, CH₂, or CH₂—CH₂, and Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂, forming:

wherein * indicates the connection point to Z₁ in formula (II) or (IIA), or Z′ in formula (III).

In the compounds of formula (II), (IIA) or (III), Y₁ can be a bond, CH₂, or CH₂—CH₂; and Y₂ can be a bond, CH₂, or CF₂, forming:

wherein * indicates the connection point to Z₁ in formula (II) or (IIA), or Z′ in formula (III).

In the compounds of formula (I), R^(1A) can be hydrogen, or C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH₃.

In the compounds of formula (I), R^(1A) can be hydrogen or CH₃.

In the compounds of formula (I), R^(1A) can be hydrogen.

In the compounds of formula (I), (II), (IIA) or (III), R¹ can be methyl, ethyl or propyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹ can be methyl.

In the compounds of formula (I), R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN.

In the compounds of formula (I), R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰.

In the compounds of formula (I), R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃ and —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (II), (IIA) or (III), R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), R² can be C₁-C₃ alkyl optionally substituted with one or two substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), R² can be C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), R² can be C₁-C₂ alkyl optionally substituted with one or two substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), R² can be:

optionally substituted with one or two substituents independently selected from OH, CF₃ and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).

In the compounds of formula (II), (IIA) or (III), R² can be:

optionally substituted with one or two substituents independently selected from OH, CF₃ and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).

In the compounds of formula (II) (IIA) or (III), R^(Z) can be:

optionally substituted with one or two substituents independently selected from OH, CF₃ and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).

In the compounds of formula (I), Y₃ can be CR⁴R⁵ or CF₂, wherein R⁴ is hydrogen or CH₃ and R⁵ is hydrogen, F, OH or CH₃; and Y₄ is CR³R⁴ or CF₂ wherein R⁴ is hydrogen or CH₃, and R³ is hydrogen, F, OH or CH₃.

In the compounds of formula (I), Y₃ can be CR⁴R⁵, wherein R⁴ is hydrogen and R⁵ is fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂; and Y₄ is CR³R⁴ wherein R⁴ is hydrogen, and R³ is fused with R⁵ to form CH₂, CH₂—CH₂ or CH₂OCH₂.

In the compounds of formula (I), Y₃ can be CR⁴R⁵, wherein R⁴ is hydrogen and R⁵ is fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂; and Y₄ is CR³R⁴ wherein R⁴ is hydrogen, and R³ is fused with R⁵ to form CH₂, CH₂—CH₂ or CH₂OCH₂, forming:

wherein * indicates the connection point to Z₁ in formula (I).

In the compounds of formula (I), X₄ can be N or C—R⁹ wherein R⁹ is hydrogen or CH₃.

In the compounds of formula (I), X₄ can be C—R⁹ wherein R⁹ is fused with R^(9A) to form CH₂ or CH₂—CH₂; and Z₁ is CH₂ or CH₂—CH₂.

In the compounds of formula (I), X₄ can be N or CH.

In the compounds of formula (II), (IIA) or (III), R³ can be hydrogen, C₁-C₃ alkyl, or fused with R⁵ to form CH₂ or CH₂—CH₂.

In the compounds of formula (II), (IIA) or (III), R³ can be hydrogen, C₁-C₂ alkyl, or fused with R⁵ to form CH₂ or CH₂—CH₂.

In the compounds of formula (II), (IIA) or (III), R³ can be hydrogen or methyl.

In the compounds of formula (II), (IIA) or (III), R⁴ can be hydrogen or C₁-C₂ alkyl.

In the compounds of formula (II), (IIA) or (III), R⁴ can be hydrogen or methyl.

In the compounds of formula (II), (IIA) or (III), R³ and R⁴ can be hydrogen.

In the compounds of formula (II), (IIA) or (III), R⁵ can be hydrogen.

In the compounds of formula (II), (IIA) or (III), R⁵ can fuse with one R³ to form CH₂—CH₂.

In the compounds of formula (I), R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl.

In the compounds of formula (I), R⁶ can be CN, F or Cl.

In the compounds of formula (I), (II), (IIA) or (III), R⁶ can be CN or Cl.

In the compounds of formula (I), (II), (IIA) or (III), R⁶ can be CN.

In the compounds of formula (II), (IIA) or (III), R⁷ can be hydrogen.

In the compounds of formula (II), (IIA) or (III), R⁷ can fuse with one R³ to form CH₂.

In the compounds of formula (I), (II), (IIA) or (III), R⁸ can be 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R⁸ can be 5-6 membered cycloalkyl, or 5-6 membered heterocycloalkyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R⁸ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R⁸ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R⁸ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl, fused with R^(8A), wherein R^(8A) can be phenyl or 6 membered heteroaryl.

In the compounds of formula (I), (II), (IIA) or (III), R⁹ can be hydrogen.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl, optionally fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopropyl, cyclobutyl, phenyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.

In the compounds of formula (II), (IIA) or (III), R¹⁰ can be 5-6 membered cycloalkyl, 5-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R^(8A).

In the compounds of formula (I, (II), (IIA) or (III), R¹⁰ can be cyclopentyl, cyclohexyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl or pyridinyl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be cyclopentyl, cyclohexyl, phenyl or pyridinyl, fused with R^(8A).

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be phenyl or pyridinyl, fused with R^(8A) wherein R^(8A) can be 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be phenyl or pyridinyl, fused with R^(8A) wherein R^(8A) can be pyrrolidinyl, pyrrolidin-2-onyl, dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be phenyl or pyridinyl, fused with R^(8A) wherein R^(8A) can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-onyl, isothiazolid-2-onyl, furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl.

In the compounds of formula (I), (II), (IIA) or (III), R¹⁰ can be phenyl or pyridinyl, fused with R^(8A) wherein R^(8A) can be tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, oxazolidinyl, isothiazolidinyl, oxozolid-2-only or isothiazolid-2-onyl.

In the compounds of formula (I), (II) or (IIA), where both Z and Z₁ are a bond, together they form a single bond.

In the compounds of formula (I), Z can be CHR^(9A), Z₁ can be CH₂, X₄ can be C—R⁹, and R⁹ can be fused with R^(9A) to form CH₂, forming:

wherein * indicates the connection point to A.

In the compounds of formula (II) or (IIA), Z can be CHR^(9A), Z₁ can be CH₂, and R⁹ can be fused with R^(9A) to form CH₂, forming:

wherein * indicates the connection point to A.

In the compounds of formula (I), (II), (IIA) or (III), R⁵ can be fused with one R³ to form CH₂—CH₂, for example forming:

wherein * indicates the connection point to Z₁ in formula (I) or Z′ in formula (II), (IIA) or (III).

In the compounds of formula (I), (II), (IIA) or (III), R⁷ can be cyclopentyl, fused with R^(8A), wherein R^(8A) can be pyridinyl, for example forming:

wherein * indicates the connection point to Y.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); and Y can be NH or O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl; and Y can be NH or O.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; and Y can be NH or O.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R¹ can be C₁-C₃ alkyl; and Y can be NH or O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); and Y can be O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl; and Y can be O.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; and Y can be O.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R¹ can be C₁-C₃ alkyl; and Y can be O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); and R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl; and R⁶ can be CN, F, Cl or CF₃.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); and R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); and R⁶ can be CN, F, Cl or CF₃.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; and R⁶ can be CN or Cl.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R¹ can be C₁-C₃ alkyl; and R⁶ can be CN or Cl.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; and Y can be NH or O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl; R⁶ can be CN, F, Cl or CF₃; and Y can be NH or O.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl;

and Y can be NH or O.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl or CF₃; and Y can be NH or O.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; R⁶ can be CN or Cl; and Y can be NH or O.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R¹ can be C₁-C₃ alkyl; R⁶ can be CN or Cl; and Y can be NH or 0.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; and Y can be O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A), wherein R^(1A) is hydrogen and R¹ is C₁-C₃ alkyl; R⁶ can be CN, F, Cl or CF₃; and Y can be O.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl;

and Y can be O.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl or CF₃; and Y can be O.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; R⁶ can be CN or Cl; and Y can be O.

In the compounds of formula (I), (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I), (II), (IIA) or (III); R¹ can be C₁-C₃ alkyl; R⁶ can be CN or Cl; and Y can be O.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; and R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; and R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; and R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; and R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I).

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; Y can be O; R⁶ can be CN or Cl; and R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (II), (IIA) or (III); Y can be O; R⁶ can be CN or Cl; and R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; Y can be O; R⁶ can be CN or Cl; and R² can be:

optionally substituted with one or two substituents independently selected from OH, CF₃ and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).

In the compounds of formula (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (II), (IIA) or (III); Y can be O; R⁶ can be CN or Cl; and R² can be:

optionally substituted with one or two substituents independently selected from OH, CF₃ and methoxy, wherein * indicates the connection point to Y in formula (II), (IIA) or (III).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰; and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I); and

Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I); and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰; and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can be CN, F, Cl or CF₃; Y can be NH or O; R² can be:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y in formula (I); and

Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I); and Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I).

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁-C₄ alkyl, —OC₃-C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I); Y₁ can be a bond or CHR⁷, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond or CHR³, wherein R³ is hydrogen, F, OH or CH₃.

In the compounds of formula (I), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹ and R^(1A); R⁶ can be CN, F, Cl, CH₃, CF₃ or cyclopropyl; Y can be NH or O; R² can be C₁-C₄ alkyl optionally substituted with one or more substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰; Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I); Y₁ can be a bond or CHR⁷, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond or CHR³, wherein R³ is hydrogen, F, OH or CH₃.

In the compounds of formula (I), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (I); R⁶ can CN, F, Cl or CF₃; Y can be NH or O; and R² can be:

optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃, —OC₃ cycloalkyl and R¹⁰, wherein * indicates the connection point to Y in formula (I); Z can be a bond,

wherein * indicates the connection point to Z₁ and ** indicates the connection point to A in formula (I); Y₁ can be a bond or CHR⁷, wherein R⁷ is hydrogen, F, OH or CH₃; and Y₂ can a bond or CHR³, wherein R³ is hydrogen, F, OH or CH₃.

In the compounds of formula (II), (IIA) or (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; and Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂.

In the compounds of formula (II), (IIA) or (III), A can be:

wherein * indicates the connection point to Z or Z′ and ** indicates the other connection point from A in formula (II), (IIA) or (III); Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; and Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂.

In the compounds of formula (II) or (IIA), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R¹; Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂; Z can be CHR^(9A); Z₁ can be CH₂; and R⁹ can be fused with R^(9A) to form CH₂.

In the compounds of formula (II) or (IIA), A can be:

wherein * indicates the connection point to Z and ** indicates the other connection point from A in formula (II) or (IIA); Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; and Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂; Z can be CHR^(9A); Z₁ can be CH₂; and R⁹ can be fused with R^(9A) to form CH₂.

In the compounds of formula (III), A can be pyrazole, 1,2,3 triazole, or 1,2,4 triazole, substituted with R₁; Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂; and Z′ can be:

wherein ** indicates the connection point to A and * indicates the other connection point from Z′.

In the compounds of formula (III), A can be:

wherein * indicates the connection point to Z′ and ** indicates the other connection point from A in formula (I); Y can be O; R⁶ can be CN or Cl; R² can be C₁-C₃ alkyl optionally substituted with one, two or three substituents independently selected from OH, methoxy, halomethyl and R¹⁰; Y₁ can be a bond, CH₂, or CH₂—CH₂; and Y₂ can be a bond, CH₂, CF₂ or CH₂—CH₂; and Z′ can be:

wherein ** indicates the connection point to A and * indicates the other connection point from Z′.

In one embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein the bond at the * position is as represented,

For example, for the compound of formula:

where the bond at the * position is as represented,

forms the compounds:

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, where the bond at the * position is as represented,

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In a further embodiment, the compounds of Formula (I) are selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

The compounds of formula (I), (II), (IIA) or (III), provided herein, or a pharmaceutically acceptable salt thereof, any or all hydrogens present in the compound, or in a particular group or moiety within the compound, may be replaced by a deuterium or a tritium. Thus, a recitation of alkyl includes deuterated alkyl, where from one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl refers to both C₂H₅ or C₂H₅ where from 1 to 5 hydrogens are replaced by deuterium, such as in C₂D_(x)H_(5-x).

The compounds of formula (I), (II), (IIA) or (III) provided herein may form pharmaceutically acceptable salts. The Examples provided herein may form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts are intended to be included. Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art (see, e.g., P. Stahl, et al. Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2^(nd) Revised Edition (Wiley-VCH, 2011); S. M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977).

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be mixed with one or more pharmaceutically acceptable carriers, diluents, or excipients. More particularly, the compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be formulated as pharmaceutical compositions. Such pharmaceutical compositions and processes for preparing the same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (A. Gennaro, et al., eds., 21st ed., Mack Publishing Co., 2005)).

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be administered by a variety of routes. Such routes of administration include oral and intravenous.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be a component in a pharmaceutical composition for the treatment of systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be a component in a pharmaceutical composition for the treatment of cancer with one or more pharmaceutically acceptable carriers, diluents, or excipients, and optionally with one or more additional therapeutic agents.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, can be combined with one or more other therapeutic agents for simultaneous, separate or sequential administration.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, and their pharmaceutical compositions can be used in the methods described herein.

The compounds of formula (I), (II), (IIA) or (III) provided herein, or a pharmaceutically acceptable salt thereof, are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 100 mg/kg of body weight. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

Certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3. For example, certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over another FGFR. For example, certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, selectively target FGFR3 over FGFR1. For example, certain compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e.g. at least about 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for FGFR3 than for FGFR1.

As used herein, the term “selectivity” of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC₅₀ value of a compound for the second target (e.g., FGFR1) by the IC₅₀ value of the same compound for the first target (e.g., FGFR3). An IC₅₀ value can be determined by any method known in the art. For example, an IC₅₀ value can be determined as described in the assays below.

As used herein, the term “cancer” refers to or describes the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.

As used herein, the term “FGFR3-associated cancer” refers to cancers associated with or having a dysregulation of the FGFR3 gene, the FGFR3 kinase protein, or expression or activity, or level of any of the same. Non-limiting examples of FGFR3-associated cancer are described herein. As used herein an “FGFR3-associated cancer” includes but is not limited to breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.

As used herein, the term “treating” (or “treatment”) refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom, condition or disorder.

As used herein, the term “patient” refers to a mammal, particularly a human.

Provided herein are methods of treating systemic sclerosis, fibrosis, pulmonary fibrosis, achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), muenke syndrome or cancer, comprising administering to a patient in need of such treatment an effective amount of the compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof.

Provided herein are methods of treating cancer, comprising administering to a patient in need of such treatment an effective amount of the compounds of formula (I), (II), (IIA) or (III), or a pharmaceutically acceptable salt thereof.

Provided in the methods herein, the cancer is selected from the group consisting of breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer. Particularly, the cancer is selected from the group consisting of breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, pancreatic cancer, prostate cancer, colorectal cancer, melanoma (e.g. cutaneous melanoma), renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, and ovarian cancer. More particularly, the cancer is selected from the group consisting of breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer) and glioblastoma. Most particularly, the cancer is bladder cancer (e.g. urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer).

The compounds provided herein can be prepared as illustrated in the preparations and examples below.

Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” refers to acetic acid; “Ac2O” refers to acetic anhydride; “aq.” refers to aqueous; “AIBN” refers to azobisisobutyronitrile; “BINAP” refers to 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; “Pd(DtBPF)Cl₂” refers to [1,1-Bis(di-tert-butylphosphino) ferrocene]dichloropalladium(II); NBS” refers to N-bromosuccinimide; “n-BuOH” refers to n-butyl alcohol or n-butanol; “BOC” refers to tert-butyloxycarbonyl; “Boc₂O” refers to di-tert-butyl dicarbonate; “BuLi” refers to butyl lithium; “CuSO₄ 5H₂O” refers to copper sulfate pentahydrate; ‘CsF” refers to cesium fluoride; “F-TEDA” refers to 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane; “CuI” refers to copper iodide; “DMP” refers to Dess-Martin periodinane; “DCE” refers to 1,2-dichloroethane; “DCM” refers to dichloromethane or methylene chloride; “DMEA” refers to dimethylethylamine; “NDM” refers to 1-dodecanethiol; “DEA” refers to diethanolamine; “DEAD” refers to diethyl azodicarboxylate; “DIAD” refers to diisopropyl azodicarboxylate; “DIEA” or “DIPEA” refers to N,N-diisopropylethylamine; “DMA” refers to N,N-dimethylaniline; “DMAP” refers to 4-dimethylaminopyridine; “DMF” refers to N,N-dimethylformamide; “DPPA” refers to diphenylphosphoryl azide; “EAA” refers to ethyl acetoacetate; “EtOAc” refers to ethyl acetate; “FA” refers to formic acid “hr” refers to hour or hours; “i-PrMgCl” refers to isopropyl magnesium chloride; “IPA” refers to isopropyl amine; “T3P” refers to propylphosphonic anhydride; “KOAc” refers to potassium acetate; “LiBH₄” refers to lithium borohydride; “LDA” refers to lithium diisopropylamide; “MsCl” refers to methanesulfonyl chloride; “MTBE” refers to methyl tert-butyl ether; “NCS” refers to N-chlorosuccinimide; “NIS” refers to N-iodosuccinimide; ‘MeMgBr” refers to methyl magnesium bromide; “NMP” refers to N-methyl-2-pyrrolidone; “—OAc” refers to acetate; “OMs” refers to methanesulfonate, also known as mesylate; “min” or “min.” refers to minute or minutes; “N₂” refers to nitrogen; “sat.” or “sat'd” refers to saturated; “soln.” refers to solution; “—OTf” refers to trifluoromethanesulfonate, also known as triflate; “PCy₃” refers to tricyclohexylphosphine; “Pd(AcO)₂” refers to palladium(II) acetate; “Pd(dba)₂” refers to bis(dibenzylideneacetone)palladium(0); “Pd₂(dba)₃” refers to tris(dibenzylideneacetone) dipalladium(0); “Pd2(dba)₃·CHCl₃” refers to tris(dibenzylideneacetone)dipalladium-chloroform adduct; “Pd(dppf)Cl₂” refers to [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II); “Pd(dppf)Cl₂·CH₂Cl₂” refers to 1,1′-bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex; “PE” refers to petroleum ether; “K₃PO₄” refers to potassium phosphate; “RT” refers to room temperature; “PPh₃” refers to triphenylphosphine; “Pd(PPh₃)₄” refers to tetrakis(triphenylphosphine)palladium(0); “Ph” refers to phenyl; “NaH” refers to sodium hydride; “TBAF” refers to tetra-n-butylammonium fluoride; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “Tf₂O” refers to trifluoromethane sulfonic anhydride; “THF” refers to tetrahydrofuran; “TsCl” refers to 4-toluenesulfonyl chloride; “TMSCF₃” refers to (trifluoromethyl)trimethylsilane; “TMSOTf” refers to trimethylsilyltrifluoro methanesulfonate; “(CF₃SO₂)₂O” refers to trifluoromethanesulfonic anhydride; “t_((R))” refers to retention time; “Xantphos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; “X-Phos” refers to 2-dicyclohexyl phosphino-2,4,6-triisopropylbiphenyl; “XPhos Pd G2” refers to chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); and “XPhos Pd G₄” refers to CAS #1599466-81-5; “ZnCl₂” refers to zinc chloride.

Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). The designations “isomer 1” and “isomer 2” refer to the compounds that elute from chiral chromatography first and second, respectively, under the conditions described herein and if chiral chromatography is initiated early in the synthesis, the same designation is applied to subsequent intermediates and examples. Where more than one chiral chromatography is conducted in the preparation, a further designation of “A” and “B” is provided where “A” refers to the compounds that elute first and “B” for those that elute second. For example “isomer 2A” refer to the first eluting compounds from the chiral chromatography of a compound previously designated “isomer 2”. Additionally, the intermediates described in the following schemes contain a number of nitrogen or oxygen protecting groups. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature (See for example “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, by Peter G. M. Wuts and Theodora W. Greene, John Wiley and Sons, Inc. 2007).

In the schemes below, all substituents, unless otherwise indicated, are as previously defined. “PG” refers to a protecting group developed for the amino group, such as carbamates and amides, an example being a BOC protecting group. Such protecting groups are well known and appreciated in the art. The reagents and starting materials are generally readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally similar compounds and the procedures described in the Preparations and Examples which follow including any novel procedures. Intermediates and processes useful for the synthesis of the compounds of formula (I), (II), (IIA) or (III) are intended to be included in this description.

Scheme 1 depicts the preparation of compounds of (4) and (8) that lead to compound 13 through different routes and will be further elaborated to formula (I). A person of skill in the art will recognize that alcohol (1) may react with a mesyl chloride to afford mesylate (2) that can be further reacted with (3) to provide (4). Treatment of compound (4) with LDA and an appropriate alkylating agent may afford compound (8). Alternatively, one skilled in the art may start with compound (3) that is substituted bromide (3) that when reacted with mesylate (2) directly affords compounds of (8).

Compound (8) can also be synthesized through an alternative route as depicted in Scheme 1. Additionally, a skilled artisan will appreciate that alcohol (1) may react under Mitsunobu conditions to provide azide (5). Azide (5) may be condensed with a beta-keto ester to afford triazole ester (6) that can undergo saponification to provide carboxylic acid (7). Treatment of carboxylic acid (7) with bromine in the presence of base affords compounds of (8).

Scheme 1 further depicts the preparation of compounds of (12) and (13) that will be further elaborated to formula (I). A skilled artisan will recognize that compounds of (4) and (8) may be deprotected to give (9) and (11) that when reacted with triflate (10) result in bromide compounds of (12) and (13). Compound (12) may further be alkylated to give compounds of (13). A skilled artisan will appreciate that ketone compounds may be substituted for the triflate compounds of (10). Alternatively, reacting compound (9) or (11) with an appropriate ketone under reductive amination conditions may also afford compounds (12) or (13).

Scheme 2 depicts an alternative preparation of compounds of (12) and (13) that will be further elaborated to formula (I). A person of skill in the art will recognize that alcohol (14) may react with mesyl chloride to afford mesylate (15) that can be further reacted with a compound (3) to provide (12). Compounds of (12) may further be alkylated to furnish compounds of (13). Alternatively, compound (3) that is substituted may be reacted with (15) to directly give compounds of (13).

Additionally, compound (13) may also be synthesized from alternative routes as depicted in Scheme 2. Alcohol (14) may react under Mitsunobu conditions to provide azide (16). Azide (16) may be condensed with a beta-keto ester to afford triazole ester (17) that can undergo saponification to provide carboxylic acid (18). Treatment of carboxylic acid (18) with bromine in the presence of base affords bromide (13). Alternatively, azide (16) may be reacted with an appropriately substituted trimethylsilylalkyne to afford trimethylsilyl analog (19). Reaction of (19) with NBS in the presence of silicon dioxide provides compounds of (13). Scheme 3

Scheme 3 depicts the preparation of compounds of formula (I). Reaction of (20) with chloroacetaldehyde provides heteroaryl chloride (21) that may be demethylated to give (22). Compound (22) may react with alcohol (23) via Mitsunobu conditions to provide a R² substituted heteroaryl chloride (24). A skilled artisan will recognize that when R² is methyl, it is unnecessary to demethylate (22) to arrive at a R² substituted (24). Conversion of heteroaryl chloride (24) to boronic acid (25) is achieved by treatment of (24) with bis(pinocolato)diboron under palladium catalyzed conditions. Boronic acid (25) may be reacted with bromide (13) to result in compounds of (26) through Suzuki coupling. Iodination of compounds of (26) in the presence of NIS provides (27) that may be further elaborated to provide R⁶ substituted compounds of (28). Alternatively, as would be known to one skilled in the art, compounds of (26) may be reacted with reagents such as NCS or NBS to afford R⁶ as chlorine or bromine directly without the intermediate iodination step to arrive at (28). Compounds of (28) are deprotected to provide compounds of (29). N-Cyanation of (29) results in N-cyanoamino compounds of formula (I).

Alternatively, a skilled artisan will appreciate that prior to conversion of (24) to boronic acid (25), compounds of (24) may first be iodinated then reacted with copper cyanide in DMF to afford a R⁶ substituted heteroaryl chloride (24). Next, the R⁶ substituted heteroaryl chloride (24) may be converted to a R⁶ substituted boronic acid R⁶ substituted (25) that can be reacted with bromide (13) to provide compounds of (28). Deprotection of (28) followed by N-cyanation results in N-cyanoamino compounds of formula (I).

Scheme 4 depicts the preparation of compounds of (37a). Reaction of (30) in the presence of 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate affords the fluorinated bicyclic analog (31). Reaction of (31) with bis(pinocolato)diboron under palladium catalyzed conditions provides the boronate ester (32). Reaction of (32) with bromide (13) under palladium catalyzed conditions affords (34). Demethylation of (34) with aqueous sodium hydroxide and dodecane-1-thiol provides hydroxy bicyclic analog (35). Alkylation of (35) with the appropriate bromide gives compound (36). Deprotection of (36) followed by N-cyanation results in N-cyanoamino compounds of (37a).

Scheme 5 depicts an alternative preparation of cyanoamino compounds of Formula (I). One of ordinary skill will recognize that compounds of (30) may be demethylated to afford (38). Demethylated (38) may be reacted with alcohol (22) under Mitsunobu conditions to provide R² substituted bromide compounds (39). Alternatively, Compound (39) may be alkylated by substituting R²OH (22) with the corresponding iodo analog R²I of (22). Conversion of R² substituted bromide (39) to boronate ester (40) may be achieved by treating (39) with bis(pinocolato)diboron under palladium catalyzed conditions. Boronate ester (40) reacted with (13) results in compounds of (28) through Suzuki coupling. Alternatively, a skilled artisan will recognize that, as depicted in Scheme 5, methylated compounds of (30) may first be treated with bis(pinocolato)diboron under palladium catalyzed conditions to provide boronate ester (41). Boronate ester (41) may be reacted with (13) to give compounds of (42) through Suzuki coupling. A skilled artisan will recognize that compounds of (42) are also compounds of (28) where R² is methyl. Lastly, compounds of (28) may be deprotected to provide amine (29). N-Cyanation of amine (28) gives N-cyanoamino compounds of formula (I).

Scheme 6 depicts an alternative preparation of compounds of formula (I) starting with compounds (42) from Scheme 5 and compounds (28) from Schemes 3 and 5 where R² is methyl. Compounds (42) are demethylated to provide compounds of (43) that are reacted with alcohol (22) under Mitsunobu conditions to provide R² substituted compounds of (28) where the R² group is not methyl. R² substituted (28) may be deprotected to give compound (29) and then N-cyanated to give N-cyanoamino compounds of formula (I).

One skilled in the art will recognize alternative reactants may also result in compounds of (28). For instance, alcohol (22) may be converted to triflate analog (R²—OTf) of (22) that may then be reacted with compounds of (43) to give compounds of (28). Additionally, alcohol compounds of (43) may first be converted to triflate compounds of (35) that may then be reacted with R²—NH₂ analogs of (22) to afford an amine-R² substituted compounds of (28).

Scheme 7 depicts the preparation of compounds of (47) that are further elaborated to cyanoamino compounds of Formula (I) in Scheme 8. Boronate ester (40), as prepared in Scheme 5, may be reacted with (8) to result in compounds of (46) through Suzuki coupling. Alternatively, a skilled artisan will recognize that boronate ester (41), as prepared in Scheme 5, may be reacted with (8) to give compounds of (44) through Suzuki coupling. A skilled artisan will recognize that boronic acid R⁶ substituted (25) as prepared in Scheme 3 may be substituted for boronic esters (40) and (41) in these reactions. Compounds of (44) may be demethylated to afford compounds of (45) that when reacted with alcohol (22) under Mitsunobu conditions afford compounds of (46). Lastly, compounds of (44) or (46) may be deprotected to provide amine (47).

A skilled artisan will recognize that amine (47) may also be prepared by replacing the R¹ substituted compounds (8) with unsubstituted compounds (4) to result in amine (47) where the A group is unsubstituted.

Scheme 8 depicts the preparation of compounds of Formula (I). Reductive amination of compounds of (47), as prepared in Scheme 7, with ketone (48) affords compounds of Formula (I). Alternatively, alkylation of (47) with triflate (49) gives compounds of Formula (I). A skilled artisan will also appreciate that mesylate (—OMs) compounds of (49) may be substituted for triflate (49).

Additionally, a skilled artisan will recognize that N-protected ketone compounds of (50) and triflate compounds of (10) may also be used instead of N-cyanoamino compounds (48) and (49). Reductive amination of compounds of (47), as prepared in Scheme 7, with N-protected ketone (50) affords N-protected (281. Alkylation of compounds of (47) with N-protected triflate (10) also affords N-protected (28). Protected (28) may be deprotected to give compounds of (29) that when reacted with cyanogen bromide result in N-cyanoamino compounds of formula (I).

Scheme 9 depicts the preparation of compounds of (54a). Compounds of R¹⁰, where R¹⁰ is a 5-6 membered aryl or a 5-6-membered heteroaryl substituted with, but not limited to a halogen, may undergo a halogen-magnesium exchange with reagents such as iPrMgCl. The resultant Grignard reagent is reacted with the TBDMS protected alcohol R² aldehyde (51) to convert the aldehyde into the alcohol (52). Protecting groups other than TBDMS may be used to protect the R² alcohol in this step. Reacting the alcohol (52) under Mitsunobu conditions provides compounds (53). Treatment of (53) under acidic conditions affords the double deprotected compound (54). Reacting (54) with cyanogen bromide results in N-cyanoamino compounds of (54a).

Scheme 10 depicts the preparation of compounds of (60a). 4,6-dichloropyridin-2-amine is reacted with a solution of 2-bromo-1,1-dimethoxypropane previously treated with aq. HCl in EtOH to afford 5,7-dichloro-3-methylimidazo[1,2-a]pyridine. The 5,7-dichloro intermediate is treated with sodium methoxide to yield 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine. The boronate ester (55) is formed by Pd catalyzed reaction of 7-chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine with bis(pinacolato)diboron. Suzuki coupling of boronate ester (55) with bromide (56) affords compound (57). Hydrolysis of (57) with NaOH gives hydroxy compound (58). Alkylation of (58) with mesylate (59) provides compound (60). Deprotection of (60) affords (61) with is cyanogen bromide to afford the N-cyanoamino compounds of (60a).

Scheme 11 depicts the preparation of (65a). Treatment of R²OH in the presence of base followed by the addition of 4,6-dichloropyridin-2-amine affords compound (61). The boronate ester (62) is formed by the Pd catalyzed reaction of compound (61) with bis(pinacolato)diboron. Suzuki coupling of boronate ester (62) and compound (13) provides compound (63). Chlorination of (63) with 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione affords compound (64) which is then deprotected under acidic conditions to give compound (65). Subsequent treatment of (65) with cyanogen bromide affords the N-cyanoamino compounds of (65a).

Scheme 12 depicts the preparation of (71a). Treatment of 7-chloro-6H-imidazo[1,2-c]pyrimidin-5-one with the boronate ester (67) under palladium catalyzed conditions provides (68). Reaction of (68) under Mitsunobu conditions affords (70). Halogenation of (70) in the presence of NCS yields (69). Deprotection of (69) affords (71). Subsequent treatment of (71) with cyanogen bromide affords compounds of (71a).

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, it will be appreciated by those skilled in the art that synthetic intermediates may be isolated and/or purified by various well known techniques as needed or desired, and that frequently, it will be possible to use various intermediates directly in subsequent synthetic steps with little or no purification. As an illustration, compounds of the preparations and examples can be isolated, for example, by silica gel purification, isolated directly by filtration, or crystallization. Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of the present invention is dependent upon the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, as is well appreciated by the skilled chemist. All substituents, unless otherwise indicated, are as previously defined, and all reagents are well known and appreciated in the art.

PREPARATIONS AND EXAMPLES Preparation 1 3-Benzyloxycyclobutanol

A mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH₄ (4.29 g, 113.5 mmol) in MeOH (50 mL) is stirred for 2 hr at RT under N₂. The reaction is quenched with H₂O at 0° C., extracted with EtOAc (3×100 mL), washed with brine (2×100 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated under reduced pressure to afford the title compound (20 g, 98.9%) as a light-yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.42-7.21 (m, 5H), 4.45 (s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H), 2.82-2.63 (m, 2H), 1.97-1.92 (m, 2H).

Preparation 2 tert-Butyl (2S,4S)-2-cyclopropyl-4-hydroxy-piperidine-1-carboxylate

To trans-2-cyclopropylpiperidin-4-ol hydrochloride (3.00 g, 16.9 mmol) in H₂O (15.00 mL) and DCM (15.00 mL) is added NaOH (2.03 g, 50.7 mmol) in portions at 0° C. under N₂. The mixture is stirred for 10 min at RT then Boc₂O (4.05 g, 18.6 mmol) is added in portions. The reaction is stirred for 2 hr at RT. The mixture is diluted with H₂O (100 mL) and extracted with DCM (2×120 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo to afford the title compound (5 g, crude) as a yellow solid, which is taken on to the next step without further purification. ¹H NMR (400 MHz, DMSO-d6) δ 4.69 (d, 1H), 3.98-3.79 (m, 2H), 3.40-3.33 (m, 1H), 2.99-2.85 (m, 1H), 1.94-1.74 (m, 2H), 1.37 (s, 9H), 1.31-1.18 (m, 2H), 1.15-1.08 (m, 1H), 0.54-0.45 (m, 1H), 0.42-0.26 (m, 2H), 0.22-0.12 (m, 1H).

Preparation 3 N-diazo-1,1,1-trifluoro-methanesulfonamide

To a solution of NaN₃ (9.22 g, 142 mmol) and hydrogen tetra(but-1-yl)ammonium sulfate (481 mg, 1.42 mmol) in distilled H₂O (30 mL) to 0° C. is added slowly a solution of (CF₃SO₂)₂O (8.00 g, 28.4 mmol) in heptane (25 mL). The reaction is stirred 1-2 hr at 0° C. Heptane (25 ml) is added to the reaction and the layers are separated. The aqueous layer is extracted with heptane (3×10 ml). The combined organic layers are dried over NaOH pellets. The organic layer is decanted and the solution is used immediately in the subsequent reaction.

Preparation 4 (1r,3r)-3-Azidocyclobutanol

A solution of (1r,3r)-3-aminocyclobutan-1-ol (1.23 g, 14.2 mmol), NaHCO₃ (4.05 g, 48.2 mmol), and CuSO₄ 5H₂O (1.77 g, 7.08 mmol) in MeOH (15 mL) and H₂O (15 mL) (v/v) is treated with a freshly prepared stock solution of N-diazo-1,1,1-trifluoro-methanesulfonamide in heptane (4.96 g, 28.3 mmol). Additional MeOH is added to the reaction in 5 mL increments until a homogeneous mixture results (20 mL total added). The reaction is stirred overnight at RT. EtOAc is added and the layers are separated. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are concentrated in vacuo to afford a dark green solution. Assumed quantitative yield. ¹H NMR (400 MHz, DMSO-d6) δ 2.05-2.31 (m, 4H) 4.07-4.18 (m, 1H) 4.29 (br s, 1H) 5.14-5.32 (m, 1H).

Preparation 5 tert-Butyl 4-(2-azido-1,1-dimethyl-ethyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl 4-(1-hydroxy-2-methylpropan-2-yl)piperazine-1-carboxylate (6.00 g, 23.22 mmol) and DBU (4.24 g, 27.87 mmol) in toluene (100 mL) is added DPPA (7.67 g, 27.89 mmol) dropwise at 0° C. under N₂. The mixture is stirred overnight at RT then concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE;EtOAc (20:1 to 10:1) to afford the title compound (6 g, 91.2%) as a light yellow oil. ES/MS m/z: 284.3 [M+H]⁺.

Preparation 6 tert-Butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate

To tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (10 g, 41.44 mmol) and PPh₃ (15.22 g, 58.01 mmol) in THF (150 ml) is added DEAD (10.10 g, 58.01 mmol) dropwise at 0° C. under N₂. The reaction is stirred 1 hr at 0° C. then DPPA (13.68 g, 49.72 mmol) is added dropwise. The reaction is stirred overnight at RT. The reaction is concentrated in vacuo then purified by silica gel chromatography, eluting with PE:EtOAc (30:1 to 20:1) to afford the title compound (14.5 g, crude) as a colorless oil which is carried forward without a further purification. ¹H NMR (300 MHz, CDCl₃) δ 3.98-3.84 (m, 1H), 3.39-3.28 (m, 4H), 2.32-2.20 (m, 2H), 1.94-1.80 (m, 2H), 1.60-1.52 (m, 4H), 1.47 (s, 9H).

The following compounds are prepared essentially as described for tert-butyl 2-azido-7-azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. DIAD can be substituted for DEAD.

TABLE 1 Prep ¹NMR (400 No. Chemical Name Structure MHz, CDCl₃), δ 7¹ tert-Butyl 4- azidoazepane-1- carboxylate

3.67-3.61 (m, 1H), 3.52-3.28 (m, 4H), 2.25-1.62 (m, 6H), 1.52 (s, 9H) 8² tert-Butyl (3R)-3- azidopiperidine-1- carboxylate

a 9  Cis-3- (Azidocyclobutoxy) methyl benzene

2.44-2.27 (m, 4H), 4.16-4.08 (m, 1H), 4.28-4.21 (m, 1H), 4.41 (s, 2H), 7.39-7.28 (m, 5H) 10   tert-butyl (2S,4R)-4- azido-2-cyclopropyl- piperidine-1- carboxylate

a 11^(3,4) tert-Butyl (3R,4S)-4- azido-3-fluoro- piperidine-1- carboxylate

4.89-4.82 (m, 1H), 4.09-4.01 (m, 1H), 3.95-3.60 (m, 2H), 3.15 (dd, 2H), 1.90-1.64 (m, 2H), 1.40 (s, 9H) 12^(4,5) tert-Butyl (3S,4S)-4- azido-3-fluoro- piperidine-1- carboxylate

4.41-4.36 (m, 1H), 4.06-3.85 (m, 2H), 3.68- 3.57 (m, 1H), 3.06- 2.97 (m, 2H), 1.93-1.83 (m, 1H), 1.40 (s, 10H) 13^(6,7) tert-Butyl (3S,4R)-4- azido-3-fluoro- piperidine-1- carboxylate

4.98-4.76 (m, 1H), 4.12-3.96 (m, 1H), 3.97- 3.64 (m, 2H), 3.26- 2.82 (m, 2H), 1.85-1.63 (m, 2H), 1.39 (s, 9 14⁴   tert-Butyl (3R,4R)-4- azido-3-fluoro- piperidine-1- carboxylate

4.63-4.24 (m, 1H), 4.09-3.83 (m, 2H), 3.80- 3.55 (m, 1H), 3.20- 2.84 (m, 2H), 2.06-1.78 (m, 1H), 1.42-1.36 (m, 10H) 15⁴   tert-butyl (3RS,4RS)- 4-azido-3-methyl- piperidine-1- carboxylate

4.02-3.84 (m, 2H), 3.38-3.27 (m, 1H), 3.02- 2.87 (m, 1H), 2.03 (d, 1H), 1.55-1.37 (m, 12H), 1.06- 0.97 (m, 3H) 16^(4,8) tert-Butyl (3RS,4SR)-4-azido- 3-methyl-piperidine- 1-carboxylate

3.97-3.89 (m, 1H), 3.47-3.38 (m, 2H), 3.37-3.29 (m, 1H), 3.28-3.16 (m, 1H), 1.90-1.79 (m, 1H), 1.67-1.55 (m, 2H), 1.43-1.33 (m, 9H), 0.87 (d, 3H) ¹Purified by Prep-TLC, PE:EtOAc (6:1 to 4:1) ²Purified by silica gel chromatography, eluting with PE:EtOAc (2:1). ³Purified by reverse phase chromatography; C18 column; eluting with 40% to 50% ACN in H₂O. ⁴ ¹H NMR (300 MHz, DMSO-d₆). ⁵Purified by silica gel chromatography, eluting with PE: EA (20:1). ⁶Purified by silica gel chromatography, eluting with PE: EA (15:1). ⁷¹H NMR (400 MHz, DMSO-d6). ⁸Purified by silica gel chromatography, eluting with PE/EA (30:1 to 20:1). a Material is used without further purification.

Preparation 17 tert-Butyl (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylate

Imidazole-1-sulfonyl azide (3.75 g, 21.63 mmol) is added to a mixture of tert-butyl (3S,4S)-4-amino-3-hydroxypiperidine-1-carboxylate (3.9 g, 18.03 mmol), K₂CO₃ (1.25 g, 9.02 mmol) and CuSO₄.5H₂O (0.45 g, 1.80 mmol) in MeOH (25 mL) at RT under N₂. The reaction is stirred overnight at RT. The reaction is quenched with H₂O and the mixture is extracted with EA (2×500 mL). The combined organic layers are washed with brine (2×3 00 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (4.3 g, crude) as a light-yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 5.67 (d, 1H), 3.95-3.77 (m, 2H), 3.48-3.35 (m, 1H), 3.33-3.17 (m, 1H), 2.67 (d, 2H), 1.89-1.80 (m, 1H), 1.39 (s, 9H), 1.24-1.16 (m, 1H).

The following compounds are prepared essentially as described for tert-butyl (3S,4S)-4-azido-3-hydroxy-piperidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. DIAD can be substituted for DEAD.

TABLE 2 Prep ¹NMR (400 MHz, No. Chemical Name Structure DMSO-d₆), δ 18 tert-Butyl (3R,4S)-4- azido-3- hydroxy- piperidine-1- carboxylate

5.50-5.13 (m, 1H), 3.75-3.69 (m, 3H), 3.67-3.58 (m, 3H), 1.80-1.68 (m, 1H), 1.62-1.52 (m, 1H), 1.38 (s, 9H) 19 tert-Butyl (3S,4R)-4- azido-3- hydroxy- piperidine-1- carboxylate

5.39 (s, 1H), 4.17- 4.03 (m, 1H), 3.68- 3.62 (m, 1H), 3.38- 3.30 (m, 4H), 1.80- 1.69 (m, 1H), 1.63- 1.53 (m, 1H), 1.39 (s, 9H). 20 tert-Butyl (3R,4R)-4- azido-3- hydroxy- piperidine-1- carboxylate

5.58 (s, 1H), 3.98- 3.86 (m, 1H), 3.85- 3.75 (m, 1H), 3.43- 3.34 (m, 1H), 3.33- 3.19 (m, 1H), 2.66- 2.57 (m, 1H), 1.89- 1.76 (m, 1H), 1.39 (s, 9H), 1.28-1.11 (m, 2H).

Preparation 21 (2S)-2-Hydroxypropanehydrazide

A mixture of ethyl lactate (3.00 g, 25.40 mmol), hydrazine hydrate (7.63 g, 152.37 mmol, 80% in H₂O) and EtOH (10.00 mL) is heated for 12 hr at 50° C. under N₂. Upon cooling to RT, the reaction is concentrated in vacuo to afford the title compound (3.0 g, crude). The title compound is taken on to the next step without further purification. ES/MS m/z: 105.2 [M+H]⁺.

Preparation 22 (2S)—N-[(E)-dimethylaminomethyleneamino]-2-hydroxy-propanamide

A mixture of (2S)-2-hydroxypropanehydrazide (3.0 g, crude), (dimethoxymethyl) dimethylamine (6.44 g, 43.22 mmol) and i-PrOH (15 mL) is heated at 50° C. for 5 hr under N₂. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with DCM:MeOH (10:1 to 8:1) to afford the title compound (3.0 g, 62.1%) as a white solid. ES/MS m/z: 160.2 [M+H]⁺.

Preparation 23 tert-Butyl 4-(4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate

A solution of 1-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine (500 mg, 2.99 mmol) in THF (3 mL) and H₂O (0.25 mL) is added TEA (605 mg, 5.98 mmol). After stirring 15 minutes BOC₂O (783 mg, 3.59 mmol) is added. The reaction is stirred at 50° C. for 15 minutes. Upon cooling to RT pH is adjusted to ˜14 by addition of 19N NaOH (aq.). The mixture is extracted with 3:1 CHCl₃:iPrOH. Organic layers are combined and washed with brine (ensuring pH remains near 12), dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a pale-yellow solid (647 mg, 2.42 mmol). ES/MS m/z: 168.1 [M+2H—BOC]⁺.

Preparation 24 2-(1-Bromoethyl)-N,N-dimethyl-benzamide

A reaction flask containing 2-ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol) and NBS (0.89 g, 5.0 mmol) is evacuated and backfilled with N₂ (3×). CCl₄ (5 mL) is added, and the reaction is stirred 2 hr at 80° C. Upon cooling to RT, the reaction is filtered, insoluble material is washed with CCl₄ (2×10 mL), then concentrated in vacuo to obtain the title compound as a clear oil (0.8 g, 70%), which is carried forward without a further purification. ¹H NMR (400 MHz, CdCl₃), δ 7.67 (m, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.25 (m, 1H), 5.45 (m, 1H), 3.18 (3H), 2.91 (3H), 2.08 (3H).

Preparation 25 2-Fluoro-N-methoxy-N-methyl-acetamide

To N,O-dimethylhydroxylamine hydrochloride (3.68 g, 37.70 mmol) under N₂ is added DCM (40 mL) and the solution is cooled to −10° C. 2M Trimethylaluminum in hexanes (2.72 g, 37.70 mmol) is slowly added to the reaction. Once the addition is complete the reaction is allowed to warm to RT and stirred at RT for 1 hr. In a separate flask ethyl-2-fluoroacetate (2.00 g, 18.85 mmol) and DCM (20 mL) is added under N₂, and the reaction mixture is cooled −10° C. Next, the solution prepared from trimethylaluminium and N,O-dimethylhydroxylamine is slowly transferred to the reaction containing ethyl-2-fluoroacetate, warmed to RT, and is stirred for 18 hr. The reaction is quenched by slowly adding 1M Rochelle's salt (10 mL). The mixture is stirred for 1 hr, diluted with H₂O, layers separated, and the aq. layer is extracted with DCM (3×10 mL). The combined organics are washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give the title compound as a light-brown oil (1.6 g, 13 mmol). ¹H NMR (400 MHz, CDCl₃) δ 3.15 (m, 3H), 3.63 (s, 3H), 5.01 (d, J=47.6 Hz, 2H).

Preparation 26 7-Fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamide

To a mixture of 7-fluoroisoquinoline-4-carboxylic acid (900 mg, 4.71 mmol), N,O-dimethylhydroxylamine hydrochloride (551 mg, 5.65 mmol) in DCM (5 mL) is added dropwise DIEA (2.43 g, 18.8 mmol). The solution is stirred for 5 min, followed by dropwise addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (4.49 g, 14.1 mmol). The mixture is stirred for 3 hr at RT, diluted with H₂O and extracted with EtOAc. The combined organic layers are dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product is purified by silica gel column chromatography column with 0% to 100% EtOAc in heptane to afford the title compound (1.03 g, 93.4%). ¹H NMR (400 MHz, CDCl₃) δ 3.47 (br s, 6H), 7.50-7.61 (m, 1H), 7.65 (dd, J=8.44, 2.20 Hz, 1H), 7.97 (dd, J=9.11, 5.07 Hz, 1H), 8.60 (s, 1H), 9.26 (s, 1H). The following compounds are prepared essentially as described for 7-fluoro-N-methoxy-N-methyl-isoquinoline-4-carboxamide using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 3 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺  27¹ N-Methoxy-N-methyl-1- (trifluoromethyl)cyclopropanecarboxamide

198.1 28 N-Methoxy-N,5-dimethyl-pyridazine-3- carboxamide

a 29 5-Chloro-N-methoxy-N-methyl- pyridazine-3-carboxamide

b  30² N,1-Dimethoxy-N-methyl- cyclopropanecarboxamide

160.2 31 N-Methoxy-N,4-dimethyl-isothiazole-5- carboxamide

c  32³ N-Methoxy-N-methyl-2- (trifluoromethoxy)acetamide

188.1  33⁴ N-methoxy-N-methyl-5- (trifluoromethoxy)pyridine-3-carboxamide

251.1 34 (4R)-N-methoxy-N,2,2-trimethyl-1,3- dioxolane-4-carboxamide

e ¹O-Dimethylhydroxylamine is used instead of HCl salt. EtOAc is used as solvent. ²Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 4:1). ³Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 1:1). ⁴Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1). a Material carried forward to next step without being characterized. b ¹H NMR (400 MHz, CDCl₃) δ 3.43 (br s, 3H), 3.84 (br s, 3H), 7.78 (br s, 1H), 9.24 (br s, 1H). c ¹H NMR (400 MHz, CDCl₃) δ 2.59 (br s, 3H), 3.37 (br s, 3H), 3.79 (br s, 3H), 8.30 (br s, 1H). d sodium 2-(trifluoromethoxy)acetate is used. e¹H NMR (400 MHz, CdCl₃) δ 1.45 (s, 3H) 1.51 (s, 3H) 3.23 (s, 3H) 3.73 (s, 3H) 4.04-4.11 (m, 1H) 4.24-4.33 (m, 1H) 4.84-4.92 (m, 1H).

Preparation 35 4-Oxopiperidine-1-carbonitrile

A solution of BrCN (256 mg, 2.42 mmol) in DCM (3.00 mL) is added dropwise to a stirred mixture of 4-piperidinone (200 mg, 2.02 mmol) and NaHCO₃ (509 mg, 6.05 mmol) in H₂O (4.50 mL) and DCM (1.50 mL) at 0° C. The mixture is stirred for 30 min at 0° C. then stirred at RT overnight. The mixture is quenched with H₂O (10 mL) and extracted with DCM (3×15 mL). The combined organic extracts are washed with sat. NaHCO₃ (3×5 mL) and brine (3×10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (120 mg, 48%). ¹H NMR (400 MHz, d₆-DMSO) δ 3.54 (t, 4H), 2.47 (t, 4H).

Preparation 36 Ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylate

A mixture of 4-bromo-1-methyl-pyrrolo[2,3-c]pyridine (500 mg, 1 mmol), diethyl oxalate (415 mg, 2.84 mmol), PdCl₂(PPh₃)₂ (9.98 mg, 14.2 μmol), and N,N-dimethylpyridin-4-amine (347 mg, 2.84 mmol) in EtOH (327 mg, 7.11 mmol) is heated at 170° C. for 1 hr with microwave irradiation. The mixture is diluted with EtOAc (10 mL) and washed with sat. aq. NH₄Cl (10 mL). The aq. layer is extracted with EtOAc (3×10 mL) and the combined organic layers are concentrated in vacuo. The residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in water to afford the title compound (265 mg, 54.8%). ES/MS m/z: 205.1 [M+H]⁺.

Preparation 37 (1-Methylpyrrolo[2,3-c]pyridin-4-yl)methanol

To a solution of ethyl 1-methylpyrrolo[2,3-c]pyridine-4-carboxylate (265 mg, 1.30 mmol) in THF (3 mL) at −78° C. is added a 1M solution of LiAlH₄ (73.9 mg, 1.95 mmol) in Et₂O. The reaction is stirred for 20 min then allowed to warm to RT and stirred for 1 hr. The mixture is diluted with Et₂O and after cooling to 0° C., H₂O (0.1 mL) is slowly added. Then a 15% aq. soln. of NaOH (0.07 mL) is added, followed by H₂O (0.2 mL), and the mixture is warmed to RT. After stirring for 15 min, MgSO₄ is added, and the mixture is stirred for an additional 15 min. The solids are removed by filtration and the filtrate is concentrated in vacuo to afford the title compound (190 mg, 90.3%). ES/MS m/z 163.1 [M+H]⁺.

Preparation 38 1-Methylpyrrolo[2,3-c]pyridine-4-carbaldehyde

To a solution of (1-methylpyrrolo[2,3-c]pyridin-4-yl)methanol (190 mg, 1.17 mmol) in DCM (4 ml) at 0° C. is added DMP (646 mg, 1.52 mmol) and the reaction is stirred for 1 hr. The mixture is diluted with DCM (10 mL) and washed with sat. aq. NaHCO₃ (10 mL) and brine (10 mL). The volatiles are removed in vacuo and the residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in water to afford the title compound (70 mg, 37%). ES/MS m/z 161.1 [M+H]⁺.

Preparation 39 2-Morpholino-5-(trifluoromethyl)pyridine-3-carbaldehyde

2-Chloro-5-(trifluoromethyl)nicotinaldehyde (700 mg, 3.34 mmol) and morpholine (291 mg, 3.34 mmol) are dissolved in EtOH (10 mL) and treated with TEA (338 mg, 3.34 mmol) at RT. The reaction is heated to 80° C. for 6 hr. The reaction is cooled to RT, concentrated in vacuo, and purified by flash silica gel chromatography eluting with a gradient of 0% to 20% MeOH in DCM to afford the title compound as a clear oil (0.7 g, 80%). ES/MS m/z 261.1 [M+H]⁺.

Preparation 40 5,7-Dichloroimidazo[1,2-a]pyridine

To a 1 L pressure tank is added 4,6-dichloropyridin-2-amine (100.00 g, 614 mmol), NaHCO₃ (154.6 g, 1840 mmol), chloroacetaldehyde (180.5 g, 920 mmol, 40% in water) and n-BuOH (500 mL) at RT under a N₂. The resulting mixture is stirred overnight at 80° C. Upon cooling to RT, the mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (8:1 to 5:1) to give the title compound as a yellow solid (88 g, 76.7%). ES/MS m/z 187.0 [M+H]⁺.

Preparation 41 5,7-Dichloro-3-methylimidazo[1,2-a]pyridine

To a solution of 2-bromo-1,1-dimethoxypropane (16.84 g, 92 mmol) in EtOH (50 mL) at RT under N₂ is added 12M HCl (33.55 g, 920 mmol). The reaction is stirred overnight at 80° C. Upon cooling to RT, the pH of the mixture is adjusted to approximately pH 8 with NaHCO₃ (90.19 g, 1074 mmol). Next, 4,6-dichloropyridin-2-amine (5.0 g, 30.68 mmol) is added to the reaction and the mixture is stirred overnight at 80° C. Upon cooling to RT, the mixture is filtered, and the filter cake is washed with EtOAc (3×100 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography, eluting with PE:EtOAc (10:1), to give the title compound as a yellow solid (2.5 g, 40.5%). ES/MS m/z 201.1 [M+H]⁺.

The following compound is prepared essentially as described for 5,7-dichloro-3-methylimidazo[1,2-a]pyridine using the appropriate reagents and adjusting the reaction temperature and time to determine completion of the reactions.

TABLE 4 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 42 7-Bromo-5-chloro- imidazo[1,2- a]pyridine

(⁷⁹Br/⁸¹Br) 231.0/233.0

Preparation 43 7-Chloro-5-methoxy-3-methylimidazo[1,2-a]pyridine

To 5,7-dichloro-3-methylimidazo[1,2-a]pyridine (1.5 g, 7.46 mmol) in MeOH (20 mL) at RT under N₂ is added NaOMe (4.03 g, 74.61 mmol). The reaction is stirred at 80° C. for 1 hr then concentrated in vacuo. The residue is diluted with H₂O (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers are washed with brine (2×30 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound as a yellow solid (1.35 g, 92.0%). ES/MS m/z 197.1 [M+H]⁺.

Preparation 44 5,7-Dichloro-3-iodo-imidazo[1,2-a]pyridine

To 5,7-dichloroimidazo[1,2-a]pyridine (5.00 g, 26.73 mmol) in DCM (50.00 mL) is added NIS (12.03 g, 53.47 mmol) in portions at RT under N₂. The reaction is stirred for 2 hr then quenched with H₂O (100 mL). The mixture is extracted with DCM (3×50 mL), organic layers are washed with brine (3×50 mL), and dried over Na₂SO₄. After filtration, the filtrate is concentrated in vacuo to afford the title compound as a dark-yellow solid (12.0 g, crude). ES/MS m/z 312.9 [M+H]⁺.

Preparation 45 6-Bromo-3-iodo-4-methoxy-pyrazolo[1,5-a]pyridine

6-Bromo-4-methoxypyrazolo[1,5-a]pyridine (0.41 g, 1.81 mmol) and NIS (609 mg, 2.71 mmol) are dissolved in ACN (8 mL) and stirred at RT for 1 hr. The suspension is filtered, and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a linear gradient of 0% to 100% EtOAc in heptane. The fractions containing the title compound is concentrated in vacuo and combined with the filtered solid to afford the title compound (0.60 g, 94.1%). ES/MS m/z (⁷⁹Br/⁸¹Br) 352.6/354.6 [M+H]⁺.

Preparation 46 6-bromo-3-fluoro-4-methoxy-pyrazolo[1,5-a]pyridine

A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5 g, 22.02 mmol) and 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (7.04 g, 22.021 mmol) in ACN (50 mL) is stirred overnight at RT under N₂. The mixture is diluted with H₂O (50 mL) then extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; mobile phase, 30% to 40% ACN in H₂O (0.1% FA), over a 10 min. period to afford the title compound (810 mg, 15.01%) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.56 (t, 1H), 8.04 (d, 1H), 6.77 (d, 1H), 3.97 (s, 3H).

Preparation 47 6-Bromo-4-methoxy-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine

A mixture of 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine (0.6 g, 1.7 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.5 g, 2.6 mmol), and CuI (0.4 g, 2.1 mmol) in DMF (6 mL) is heated for 6 hr. to 80° C. The suspension is filtered and the filtrate is concentrated in vacuo. The residue is purified by normal phase chromatography eluting with a linear gradient of 0% to 100% EtOAc in heptane to afford the title compound (0.125 g, 20%) as a white solid. ES/MS m/z 249.9 [M+H]⁺.

Preparation 48 5,7-Dichloroimidazo[1,2-a]pyridine-3-carbonitrile

To of 5,7-dichloro-3-iodoimidazo[1,2-a]pyridine (11.00 g, 35.15 mmol) in DMF (50.00 mL) is added in portions CuCN (6.30 g, 70.31 mmol) at RT under N₂. The reaction is stirred for 2 hr at 100° C. Upon cooling to RT, NH₄OH (100 mL) is added dropwise over 5 minutes. The mixture is diluted with H₂O (300 mL), stirred for 2 hr, then extracted with DCM (3×400 mL). The combined organic layers are washed with brine (3×300 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (5:1 to 1:2), to afford the title compound as a yellow solid (3.5 g, 47.0%). ES/MS m/z (³⁵Cl/³⁷Cl) 211.9/213.9 [M+H]⁺.

Preparation 49 6-Bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile

A stirred solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (5.60 g, 22.22 mmol) and NDM (5.39 g, 26.66 mmol) in DMA (20.0 mL) is treated with NaOH (5.33 g, 66.65 mmol, 50% in H₂O) at RT under N₂, and the mixture is stirred for 2 hrs at 50° C. under N₂. The mixture is diluted with H₂O (200 mL), acidified to pH 4-5 with conc. HCl, and extracted with EtOAc (3×200 mL). The combined organic extracts are washed with brine (3×100 mL) and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1) to give the title compound as a yellow solid (4.6 g, 90.7%) ES/MS m/z 235.9/237.9 [M−H]⁻.

Preparation 50 6-Bromo-4-isopropoxy-pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 6-bromo-4-hydroxy-pyrazolo[1,5-a]pyridine-3-carbonitrile (200 mg, 0.84 mmol) and Cs₂CO₃ (410.63 mg, 1.26 mmol) in DMF (2 mL) is treated with 2-iodopropane (0.1 mL, 1 mmol) and stirred for 7.5 hrs. The reaction mixture is purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc (0-100%) to give the title compound as a light-yellow solid (174.2 mg, 0.62 mmol, 74.02%). ES/MS m/z 282.00 [M+H]⁺.

Preparation 51 2-[3-[tert-Butyl(dimethyl)silyl]oxyazetidin-1-yl]-5-(trifluoromethyl)pyridine-3-carbaldehyde

2-Chloro-5-(trifluoromethyl)nicotinaldehyde (575 mg, 2.74 mmol) and 3-((tert-butyldimethylsilyl)oxy)azetidine (566 mg, 3.02 mmol) are dissolved in EtOH (8 mL) and treated with NEt₃ (305 mg, 3.02 mmol) at RT. The reaction is heated for 4 hr at 80° C. Upon cooling to RT, the reaction is concentrated and purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to obtain the title compound (0.73 g, 2.03 mmol, 74%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 4.75 (m, 1H), 4.50 (m, 2H), 4.08 (m, 2H), 0.91 (s, 9H), 0.09 (s, 6H).

Preparation 52 1-(4-Isoquinolyl)ethanol

To a solution of isoquinoline-4-carbaldehyde (500 mg, 3.18 mmol) in anhydrous THF (7 mL) at 0° C. is added 3M methylmagnesium bromide (455 mg, 3.82 mmol). The reaction is stirred at 0° C. for 20 minutes, allowed to warm to RT, then stirred for 2 hr at RT. The reaction is quenched with sat. NH₄Cl, extracted with EtOAc (3×30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% in heptane to give the title compound. (540 mg, 98.0%). ¹H NMR (400 MHz, CDCl₃) δ 1.73 (d, J=6.48 Hz, 3H), 2.72 (br s, 1H), 5.59 (q, J=6.48 Hz, 1H), 7.63 (ddd, J=8.10, 7.00, 1.04 Hz, 1H), 7.75 (ddd, J=8.47, 6.94, 1.34 Hz, 1H), 7.99 (d, J=8.07 Hz, 1H), 8.18-8.22 (m, 1H), 8.61 (s, 1H), 9.15 (s, 1H).

The following compounds are prepared essentially as described for 1-(4-isoquinolyl)ethanol using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.

TABLE 5 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 53 1-(1-Isopropyltriazol-4- yl)ethanol

a 54 1-(2-Ethyltriazol-4-yl)ethanol

b 55 1-(3-Ethyltriazol-4-yl)ethanol

c 56 1-(6-Methylpyrazin-2- yl)ethanol

d 57 1-[2-Morpholino-5- (trifluoromethyl)-3- pyridyl]ethanol

e 58 1-(5-Methyl-1,3,4-thiadiazol-2- yl)ethanol

f 59 1-Isothiazol-5-ylethanol

g 60 1-(3- Methylsulfonylphenyl)ethanol

h 61 1-(5-Fluoro-3-pyridyl)ethanol

i 62 1-(5-Chloro-3-pyridyl)ethanol

158.2 63 1-(1-Methylpyrrolo[2,3- c]pyridin-4-yl)ethanol

177.1 64 1-[2-Chloro-5- (trifluoromethyl)-3- pyridyl]ethanol

j 65 1-[2-[3-[tert- Butyl(dimethyl)silyl]oxyazetidin- 1-yl]-5-(trifluoromethyl)-3- pyridyl]ethanol

k a¹H NMR (400 MHz, CDCl₃) δ 1.55-1.67 (m, 9H), 2.80 (br s, 1H), 4.14 (q, J = 6.77 Hz, 1H), 4.84 (dt, J = 12.96, 6.36 Hz, 1H), 5.11 (q, J = 5.91 Hz, 1H), 7.50 (s, 1H). b¹H NMR (400 MHz, d₆-DMSO) δ 1.35-1.46 (m, 6H), 4.37 (m, 2H), 4.81 (m, 1H), 5.30 (br s, 1H), 7.61 (br s, 1H). c¹H NMR (300 MHz, d₆-DMSO) δ 7.58 (s, 1H), 5.50 (d, 1H), 4.95-4.85 (m, 1H), 4.50-4.32 (m, 2H), 1.56-1.38 (m, 6H). d¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.39 (s, 1H), 4.91-5.02 (m, 1H), 2.59 (s, 3H), 1.56 (br d, J = 6.36 Hz, 3H). e¹H NMR (400 MHz, CDCl₃) δ 1.57 (br d, J = 6.11 Hz, 3H), 3.24 (br s, 4H), 3.48 (br s, 1H), 3.87 (br s, 4H), 5.08-5.19 (m, 1H), 7.92 (br s, 1H), 8.51 (br s, 1H). f ¹H NMR (400 MHz, CDCl₃) δ 1.66 (br d, J = 6.11 Hz, 3H), 2.73-2.80 (m, 3H), 2.97-3.27 (m, 1H), 5.21-5.35 (m, 1H). g¹H NMR (400 MHz, CDCl₃) δ 8.41-8.29 (m, 1H), 7.13-7.03 (m, 1H), 5.34-5.21 (m, 1H), 1.62 (t, 3H). h¹H NMR (400 MHz, CDCl₃) δ 1.55 (d, J = 6.7 Hz, 3H), 3.08 (s, 3H), 4.96-5.07 (m, 1H), 7.52-7.61 (m, 1H), 7.68 (br t, J = 6.8 Hz, 1H), 7.78-7.91 (m, 1H), 7.96-8.01 (m, 1H). i¹H NMR (400 MHz, CDCl₃) δ 8.36 (t, 1H), 8.32 (d, 1H), 7.62-7.39 (m, 1H), 4.99 (q, 1H), 2.82 (s, 1H), 1.53 (d, 3H). j¹H NMR (400 MHz, CDCl₃) δ 8.56 (s, 1H), 8.32 (s, 1H), 5.28 (m, 1H), 1.54 (d, 3H). k¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.84 (s, 1H), 4.95 (m, 1H), 4.73 (m, 1H), 4.39 (m, 2H), 4.04 (m, 2H), 1.50 (d, 3H), 0.90 (s, 9H), 0.09 (s, 6H).

Preparation 66 1-(5-Fluoro-3-methyl-2-pyridyl)ethanone

To 2-bromo-5-fluoro-3-methylpyridine (3 g, 15.8 mmol) in toluene (50 mL) is added i-PrMgCl (12 mL, 23.7 mmol, 2 M in THF) dropwise at RT under N₂. After stirring 3 hr at RT, N-methoxy-N-methylacetamide HCl (2.4 g, 23.7 mmol) is added. The reaction is stirred 2 hr then quenched with H₂O (100 mL). The mixture is extracted with EtOAc (3×100 mL). The organic layers are combined, washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to give the title compound (2 g, 83%). ES/MS m/z 154.1 [M+H]⁺.

The following compounds are prepared essentially as described for 1-(5-fluoro-3-methyl-2-pyridyl)ethanone using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.

TABLE 6 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 67 2,2-Difluoro-1-(5-fluoro-2- pyridyl)ethanone

174.0 [M − H] 68 (5-Fluoro-2-pyridyl)-[1- (trifluoromethyl)cyclopropyl] methanone

233.8  69¹ (5-Fluoro-2-pyridyl)-(1- methoxycyclopropyl) methanone

196.1  70² 1-[5-(trifluoromethoxy)-3- pyridyl]ethanone

205.9 ¹Purified by silica gel column chromatography, eluting with PE:EA (12:1 to 10:1). ²Purified by silica gel column chromatography, eluting with PE:EA (20:1 to 4:1).

Preparation 71 1-(7-Fluoro-4-isoquinolyl)ethanone

To a solution of 7-fluoro-N-methoxy-N-methylisoquinoline-4-carboxamide (500 mg, 2.13 mmol) in THF (10 mL) at 0° C. is added dropwise a solution of 3M MeMgBr in Et₂O (255 mg, 2.13 mmol, 0.71 ml). The reaction is stirred at 0° C. for 20 min, then allowed to warm to RT and stirred for an additional 2 hr. The reaction is quenched with sat. aq. NH₄Cl solution. Layers are separated and the aq. layer is extracted with EtOAc. Combined organics are dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a gradient of 0% to 10% MeOH in DCM to give the title compound (389 mg, 96.3%). ¹H NMR (400 MHz, CDCl₃) δ 2.81 (s, 3H), 7.59-7.67 (m, 2H), 8.99 (dd, J=9.11, 5.32 Hz, 1H), 9.05 (s, 1H), 9.33 (s, 1H).

The following compounds are prepared essentially as described for 1-(7-Fluoro-4-isoquinolyl)ethanone using the appropriate reagents and adjusting the reaction temperature and times to determine completion of the reactions.

TABLE 7 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 72¹ 1-(5-Methylpyridazin- 3-yl)ethanone

a 73  1-(5-Chloropyridazin- 3-yl)ethenone

b 74¹ 1-(4-Methylisothiazol- 5-yl)ethanone

c ¹Purified by flash chromatography eluting with 0% to 100% EtOAc in heptane. a¹H NMR (400 MHz, d₆-DMSO) δ 2.42 (s, 3H), 2.77 (s, 3H), 7.96 (br s, 1H), 9.31 (br s, 1H). b¹H NMR (300 MHz, d₆-DMSO) δ 9.63 (br s, 1H), 8.26 (br s, 1H), 2.79 (br s, 3H). c¹H NMR (400 MHz, CDCl₃) δ 2.54 (br s, 3H), 2.60 (br s, 3H), 8.35 (br s, 1H).

Preparation 75 2-Fluoro-1-(5-fluoro-2-pyridyl)ethanone

A solution of 2-bromo-5-fluoropyridine (1.1 g, 6.3 mmol) in toluene (6 mL) is cooled to −78° C. under N₂ then a soln of n-BuLi (0.44 g, 2.8 ml, 6.9 mmol, 2.5M in hexanes) is slowly added. The reaction mixture is then stirred at −78° C. for 30 min. 2-Fluoro-N-methoxy-N-methylacetamide (0.83 g, 6.9 mmol) in toluene (2.0 mL) is added to the reaction. After stirring at −78° C. for 30 min the cooling bath is removed, and the reaction is quenched with sat. aq NH₄Cl and extracted with DCM. The organic layer is washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to obtain the title compound (0.9 g, 90%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 5.77 (d, J=47.6 Hz, 2H) 7.46-7.55 (m, 1H) 8.05-8.12 (m, 1H) 8.39-8.44 (m, 1H)

Preparation 76 1-[5-Fluoro-6-(2-methoxyethoxy)-2-pyridyl]ethanone

To 6-bromo-3-fluoro-2-(2-methoxyethoxy)pyridine (1.7 g, 6.80 mmol) in THF (50 mL, 617.2 mmol) is added n-BuLi (2.72 mL, 6.80 mmol, 2.5 M in hexane) dropwise at −78° C. under N₂. The reaction is stirred for 0.5 hr at −78° C. Next, N-methoxy-N-methylacetamide (2.10 g, 20.39 mmol) is added and stirring continues for an additional 1 hr at −78° C. The reaction is quenched by the addition of H₂O (50 mL) at −78° C. Upon warming to RT the reaction is extracted with EtOAc (3×50 mL). Organic layers are combined and washed with brine (3×50 mL), dried over Na₂SO₄, filtered and the filtrate is concentrated in vacuo. The residue is used in a subsequent step directly without further purification. ES/MS m/z 213.9 [M+H]⁺.

The following compound is prepared essentially as described for 1-[5-Fluoro-6-(2-methoxyethoxy)-2-pyridyl]ethanone using the appropriate reagents and adjusting the reaction temperature and time to determine completion of the reaction.

TABLE 8 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 77 [(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]-(5-fluoro-2-pyridyl)methanone

a a¹H NMR (400 MHz, CdCl₃) δ 1.43 (s, 3H) 1.47 (s, 3H) 3.92 (dd, J = 8.56, 6.48 Hz, 1H) 4.50-4.59 (m, 1H) 5.61-5.68 (m, 1H) 7.45-7.54 (m, 1H) 8.08-8.15 (m, 1H) 8.39-8.44 (m, 1H).

Preparation 78 (1E)-2-Bromobenzaldehyde oxime

A mixture of 2-bromobenzaldehyde (10 g, 54.05 mmol) and NH₂OH·HCl (4.1 g, 59.45 mmol) in EtOH (100 mL) is stirred for 2 hr at 80° C. under N₂. The reaction is concentrated in vacuo. The residue is dissolved in EtOAc (100 mL) and washed with H₂O (3×50 mL). The combined organic layers are dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as an off-white solid (12 g) which is carried forward without a further purification. ES/MS m/z (⁷⁹Br/⁸¹Br) 200/202 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.32 (s, 1H), 7.80 (dd, 1H), 7.67 (dd, 1H), 7.45-7.38 (m, 1H), 7.34 (td, 1H).

Preparation 79 3-(2-Bromophenyl)isoxazole

To a stirred solution of (E)-N-[(2-bromophenyl)methylidene]hydroxylamine (5 g, 25.00 mmol) and NCS (4.33 g, 32.49 mmol) in CCl₄ (50 mL) is added calcium carbide (11.19 g, 175.00 mmol) and H₂O (6.30 g, 349.93 mmol) dropwise at RT under N₂. The reaction is stirred overnight. The suspension is filtered, the filter cake is washed with DCM (3×30 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (12:1) to afford the title compound as an off-white solid (3.5 g, 62.50%). ES/MS m/z (⁷⁹Br/⁸¹Br) 224/226 [M+H]⁺.

Preparation 80 2-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyrazine

To a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (2000 mg, 10.957 mmol) and tributyl(1-ethoxyethenyl)stannane (4748.68 mg, 13.148 mmol) in dioxane (25 mL) is added Pd(PPh₃)₄ (1266.16 mg, 1.096 mmol) at RT under N₂. The resulting mixture is stirred for 4 hr at 80° C. The mixture is allowed to cool down to RT and is concentrated under vacuum. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (8:1 to 4:1) to afford the title compound as a yellow oil (1.8 g, 75.29%). ¹H NMR (300 MHz, d₆-DMSO) δ 9.18-9.16 (m, 2H), 5.47-5.41 (m, 1H), 4.75-4.69 (m, 1H), 4.03 (q, 2H), 1.40 (t, 3H).

The following compound is prepared essentially as described for 2-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyrazine using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

TABLE 9 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 81¹ 3-[2-(1- Ethoxyvinyl) phenyl]isoxazole

216.1 ¹Purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 5:1).

Preparation 82 1-(2-Isoxazol-3-ylphenyl)ethanone

To 3-[2-(1-ethoxyethenyl)phenyl]-1,2-oxazole (2.20 g, 10.22 mmol) in MeOH (20 mL) is added 4M HCl in MeOH (20 mL) at RT. The reaction is stirred for 1 hr under N₂. The reaction is quenched with H₂O (100 mL). The mixture is extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (3:1) to afford the title compound as a yellow oil (1.6 g, 83.6%). ES/MS m/z 188.1 [M+H]⁺.

Preparation 83 1-[6-(Trifluoromethyl)pyrazin-2-yl]ethanone

A mixture of 2-(1-ethoxyethenyl)-6-(trifluoromethyl)pyrazine (1.20 g, 5.50 mmol) and 12 M HCl (2.29 mL, 27.50 mmol) in THF (20 mL) is stirred for 2 hr at RT under N₂. The resulting mixture is concentrated in vacuo to afford the title compound which is carried forward without a further purification. ¹H NMR (400 MHz, d₆-DMSO) δ 9.45 (s, 1H), 9.41 (s, 1H), 2.67 (s, 3H).

Preparation 84 2-Methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanone

A solution of i-PrMgCl (3.3 mL, 6.61 mmol) is added dropwise under N₂ at 0° C. to a solution of 3-bromo-5-(trifluoromethyl)pyridine (1.00 g, 4.42 mmol) in dry THF (40 mL). The solution is stirred for 1 hr under N₂ at 50° C. To the above solution is added N-2-dimethoxy-N-methylacetamide (1.18 g, 8.86 mmol) in dry THF (1 mL) under N₂ at RT. The solution is stirred for 2 hr under N₂ at RT. The residue is acidified to pH 6 with conc. aq HCL. The mixture is diluted with H₂O (50 mL), the pH adjusted to 11 with solid Na₂CO₃, and extracted with EtOAc (3×50 mL). The organic layers are combined, washed with brine (3×50 mL), and dried over anhydrous Na₂SO₄. The mixture is filtered and the filtrate is concentrated under reduced pressure. The crude product (5.00 g) is used without further purification. ¹H NMR (300 MHz, CDCl₃) δ 9.38-9.30 (d, 1H), 9.14-9.05 (m, 1H), 8.56-8.48 (m, 1H), 4.69 (s, 2H), 3.55-3.53 (in, 3H).

The following compounds are prepared essentially as described for 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanone using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 10 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 85 3,3,3-Trifluoro-1-(5-fluoro-2- pyridyl)propan-1-one

a  86¹ 2-Pyridyl-[1-(trifluoromethyl) cyclopropyl]methanone

216.1  87² 1-(5-Fluoro-2-pyridyl)-2-methoxy- ethanone

170.1 88 1-(5-Fluoro-2-pyridyl)-2- (trifluoromethoxy)ethanone

b ¹2.5M BuLi used instead of iPrMgCl. Reaction run in toluene at −78° C. ²Purification by silica gel column chromatography, eluting with PE:EtOAc (12:1). a¹H NMR (400 MHz, CDCl₃) δ 5.83 (d, J = 47.6 Hz, 2H), 7.54-7.61 (m, 1H), 8.15 (dd, J = 8.68, 4.65 Hz, 1H), 8.47 (s, 1H). b Material is used without further purification.

Preparation 89 2-Methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanol

NaBH₄ (860 mg, 22.73 mmol) is added in portions at RT under N₂ to a stirred mixture of 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanone (5.00 g) in MeOH (20 mL). The reaction is quenched with H₂O (5 mL) at RT and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 2:1) to give the title compound (500 mg, 9.91%) as a yellow liquid. ES/MS m/z 222.0 [M+H]⁺.

The following compounds are prepared essentially as described for 2-methoxy-1-[5-(trifluoromethyl)pyridin-3-yl]ethanol using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 11 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺  90¹ 1-(5-Methylpyridazin-3- yl)ethanol

a  91¹ 2-Fluoro-1-(5-fluoro-2- pyridyl)ethanol

b  92¹ 1-(7-Fluoro-4- isoquinolyl)ethanol

c  93 1-[6- (Trifluoromethyl)pyrazin- 2-yl]ethanol

d  94 1-(2-Pyridyl)propan-1-ol

138.1  95 1-(5-Chloropyridazin-3- yl)ethanol

e  96 1-(5-Methyl-3- pyridyl)ethanol

f  97 1-[5-(Difluoromethyl)-3- pyridyl]ethanol

g  98 3,3,3-Trifluoro-1-(5- fluoro-2-pyridyl) propan-1-ol

210.1  99 (5-Fluoro-2-pyridyl)-(1- methoxycyclopropyl) methanol

198.1  100² 2-Pyridyl-[1- (trifluoromethyl) cyclopropyl]methanol

218.0 101 1-(2- Methylsulfonylphenyl) ethanol

183.1 [M − OH]⁺ 102 1-(5-Fluoro-3-methyl-2- pyridyl)ethanol

156.1  103³ 2,2-Difluoro-1-(5-fluoro- 2-pyridyl)ethanol

178.3  104⁴ 1-(2-Isoxazol-3- ylphenyl)ethanol

188.0 [M − H]⁻ 105 1-(5-Fluoro-2-pyridyl)-2- methoxy-ethanol

172.1 106 1-(2-Isothiazol-3- ylphenyl)ethanol

h  107¹ 1-(4-Methylisothiazol-5- yl)ethanol

i 108 1-(5-Fluoro-2-pyridyl)-2- (trifluoromethoxy) ethanol

226.1 109 1-[5-Fluoro-6-(2- methoxyethoxy)-2- pyridyl]ethanol

216.1 110 1-[5-(trifluoromethoxy)- 3-pyridyl]ethanol

208.0 111 [(4R)-2,2-dimethyl-1,3- dioxolan-4-yl]-(5-fluoro- 2-pyridyl)methanol

j 112 (5-Fluoro-2-pyridyl)-[1- (trifluoromethyl) cyclopropyl]methanol

236.0 ¹Purified by silica gel column chromatography, eluting with 0% to 100% EtOAc in heptane. ²Purified by silica gel column chromatography, eluting with PE:EtOAc (6:1 to 2:1). ³Purified by silica gel column chromatography, eluting with PE:EtOAc (9:1). ⁴Purified by silica gel column chromatography, eluting with PE:EtOAc (1:1). ⁵Purified by silica gel column chromatography, eluting with a gradient of 0% to 100% EtOAc in heptane. a¹H NMR (400 MHz, d₆-DMSO) δ 1.41 (d, J = 6.60 Hz, 3H), 2.33 (s, 3H), 4.93 (qd, J = 6.56, 4.65 Hz, 1H), 5.59 (d, J = 4.65 Hz, 1H), 7.58 (d, J = 0.98 Hz, 1H), 8.97 (d, J = 2.08 Hz, 1H). b¹H NMR (400 MHz, CdCl₃) δ ppm 4.61 (dd, J = 47.2, 5.3 Hz, 2H) 5.02 (dt, J = 16.1, 5.3 Hz, 1H) 7.46-7.53 (m, 2H) 8.46 (s, 1H). c¹H NMR (400 MHz, CDCl₃) δ 1.73 (d, J = 6.48 Hz, 3H), 2.42 (br s, 1H), 5.56 (q, J = 6.56 Hz, 1H), 7.50-7.57 (m, 1H), 7.61 (br d, J = 8.68 Hz, 1H), 8.29 (dd, J = 9.23, 5.20 Hz, 1H), 8.59 (s, 1H), 9.13 (s, 1H). d¹H NMR (400 MHz, d₆-DMSO) δ 9.11 (s, 1H), 9.07 (s, 1H), 5.82 (d, 1H), 4.95-4.88 (m, 1H), 1.44 (d, 3H). e Material is used without further purification. f¹H NMR (400 MHz, CDCl₃) δ 1.51 (br d, J = 6.11 Hz, 3H), 2.34 (s, 3H), 2.75-2.90 (m, 1H), 4.87-4.97 (m, 1H), 7.55 (br s, 1H), 8.31 (br s, 1H), 8.36 (br s, 1H). g¹H NMR (400 MHz, CDCl₃) δ 1.56 (br d, J = 6.24 Hz, 3H), 2.54 (br s, 1H), 5.04 (q, J = 5.79 Hz, 1H), 6.72 (t, J = 55.8 Hz, 1H,) 7.91 (br s, 1H), 8.65 (br s, 1H), 8.72 (br s, 1H). h¹H NMR (400 MHz, CDCl₃) δ 1.55 (d, J = 6.6 Hz, 3H) 4.95 (q, J = 6.6 Hz, 1H) 7.37-7.46 (m, 1H) 7.46-7.52 (m, 2H) 7.53-7.59 (m, 1H) 7.66 (br d, J = 7.58 Hz, 1H) 8.79 (d, J = 4.65 Hz, 1H). i¹H NMR (400 MHz, CdCl₃) δ 2.54-2.58 (m, 3H), 2.61-2.64 (m, 3H), 3.39 (m, 1H), 3.80 (m, 1H), 8.37 (br s, 1H). j¹H NMR (400 MHz, CdCl₃) δ 1.35 (s, 3H) 1.44 (s, 3H) 3.92-3.98 (m, 1H) 4.00-4.07 (m, 1H) 4.40-4.47 (m, 1H) 4.76-4.80 (m, 1H) 7.42-7.55 (m, 2H) 8.41-8.46 (m, 1H)

Preparation 113 Cis-3-Benzyloxycyclobutanol

A mixture of 3-(benzyloxy)cyclobutan-1-one (20 g, 113.5 mmol) and NaBH₄ (4.29 g, 113.5 mmol) in MeOH (50 mL) is stirred for 2 hr at RT under N₂. The reaction is quenched with H₂O at 0° C., extracted with EtOAc (3×100 mL), washed with brine (2×100 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated under reduced pressure to afford the title compound (20 g, 98.9%) as a light-yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.42-7.21 (m, 5H), 4.45 (s, 2H), 3.93-3.85 (m, 1H), 3.71-3.62 (m, 1H), 2.82-2.63 (m, 2H), 1.97-1.92 (m, 2H).

Preparation 114 3-(5-Fluoro-2-pyridyl)-3-hydroxy-2,2-dimethyl-propanenitrile

Lithiumdiisopropylamide in THF (2.57 g, 24.0 mmol, 2M in THF) is slowly added to a cooled solution of isobutyronitrile (1.66 g, 24.0 mmol) in THF (25 mL) at −78° C. under N₂. The reaction is stirred at −78° C. for 30 minutes. Next, 5-fluoro picolinaldehyde (2.00 g, 16.0 mmol) in THF (6 mL) is slowly added to the reaction. After stirring for an additional hour, the reaction is allowed to warm to RT. The reaction is quenched with sat. NH₄Cl, extracted in EtOAc, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue is purified by phase silica gel flash chromatography eluting with a gradient of 0% to 100% EtOAc in Heptane to afford the title compound (1.60 g, 51.5%) as a white solid. ¹H NMR (400 MHz, CdCl₃) δ 8.46 (s, 1H), 7.55-7.47 (m, 2H), 4.68 (s, 1H), 4.54 (brs, 1H), 1.44 (s, 3H), 1.21 (s, 3H).

Preparation 115 2,2,2-Trifluoro-1-(5-fluoropyridin-2-yl)ethanol

To 5-fluoropyridine-2-carbaldehyde (2 g, 15.99 mmol) and TMSCF₃ (3.41 g, 23.98 mmol) in THF (5.00 mL) is added TBAF (3.20 mL, 3.200 mmol) dropwise at 0° C. under N₂. The resulting mixture is stirred at RT for 3 hr then concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with 50% EtOAc in PE to afford the title compound as a white solid (2 g, 64.12%). ES/MS m/z 196.1 [M+H]⁺.

Preparation 116 2-[tert-Butyl(dimethyl)silyl]oxy-1-(4-isoquinolyl)ethanol

To 4-bromoisoquinoline (2.00 g, 9.61 mmol) dissolved in THF (8 mL) under N₂ is added dropwise 2M isopropylmagnesium chloride (1.48 g, 14.42 mmol) at RT. The reaction is stirred 30 minutes at RT, then 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (3.35 g, 19.23 mmol) is added dropwise. The reaction is stirred at RT for 2 hr, then is quenched with aq. sat. NH₄Cl. The mixture is extracted with EtOAc (2×100 mL). The combined organic layers are dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane. The isolated material is further purified by silica gel chromatography eluting with 20% DCM in EtOAc to afford the title compound which is contaminated with the isoquinoline biproduct (400 mg, 13.7%). ¹H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.93 (s, 9H), 3.72-3.91 (m, 1H), 3.99 (dd, J=10.27, 3.42 Hz, 1H), 5.47 (dd, J=8.38, 3.36 Hz, 1H), 7.58-7.78 (m, 7H), 7.84 (d, J=8.31 Hz, 2H), 7.96-8.04 (m, 2H), 8.12 (d, J=8.44 Hz, 1H), 8.54 (d, J=5.62 Hz, 1H), 8.70 (s, 1H), 9.22 (s, 1H), 9.27 (s, 1H).

Preparation 117 2-[(tert-Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol

A solution of i-PrMgCl (5.11 mL, 10.23 mmol, 2 M in THF) is added dropwise at 0° C. under N₂ to a stirred solution of 2-bromo-5-fluoropyridine (1.2 g, 6.82 mmol) in toluene (10.00 mL). The mixture is stirred for 30 min at 0° C. under N₂. 2-[(tert-Butyldimethylsilyl)oxy] acetaldehyde (1.78 g, 10.23 mmol) is added dropwise over 10 min at 0° C. to the mixture. The mixture is stirred 2 hr at 0° C. The reaction is quenched with H₂O and extracted with EtOAc (3×20 mL). The combined organic layers are washed with brine (2×10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1) to give the title compound (420 mg, 22.69%) as a colorless oil. ES/MS m/z 272.2 [M+H]⁺

The following compounds are prepared essentially as described for 2-[(tert-Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 12 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 118  2-[tert-Butyl(dimethyl)silyl]oxy-1- [5-(trifluoromethyl)-3- pyridyl]ethanol

322.1 119¹ 2-[tert-Butyl(dimethyl)silyl]oxy-1- (3,5-difluoro-2-pyridyl)ethanol

290.1 120  3-[tert-Butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)propan-1-ol

286.2 121² 2-[tert-Butyl(dimethyl)silyl]oxy-1- (5-chloro-2-pyridyl)ethanol

288.1 122  Cyclopropyl-(5-fluoro-2- pyridyl)methanol

150.0 [M − OH]⁺ 123  (1-Fluorocyclopropyl)-(5-fluoro-2- pyridyl)methanol

a 124³ 2-[tert-Butyl(dimethyl)silyl]oxy-1- (2-pyridyl)ethanol

254.0 ¹Purified by silica gel column chromatography, eluting with PE:EtOAc (20:01 to 10:1). ²Purified by silica gel column chromatography, eluting with PE:EtOAc (5:1-3:1). ³Quenched with saturated NH₄Cl. a¹H NMR (400 MHz, DMSO-d6) δ 0.78-1.04 (m, 4H), 4.56-4.64 (m, 1H), 6.00 (d, J = 5.01 Hz, 1H), 7.52-7.78 (m, 2H), 8.52 (d, J = 2.69 Hz, 1H.)

Preparation 125 2-[(tert-Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 1 and 2-[(tert-Butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 2

Separation of the 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (70 g, 257.915 mmol) enantiomers is performed using the following conditions: Column: CHIRALPAK IG, 7*25 cm, 10 m; eluting with 60% ACN in H₂O (0.05% diethylamine); Flow rate: 200 mL/min; 266/204/208 nm; to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 1, t_((R)) is 7.5 min (20.0 g) and 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2, t_((R)) is 11.2 min (20.5 g).

2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 1 is further purified by silica gel column chromatography, eluting with PE/EA (20:1 to 4:1) to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 1 (15.0 g, 21% yield) with 98.6% ee, ES/MS m/z 272.1 [M+H]⁺.

2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2 is further purified by silica gel column chromatography, eluting with PE/EA (30:1 to 20:1) to afford 2-[(tert-Butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol, Isomer 2 (14.0 g, 20% yield) with 93.1% ee, ES/MS m/z 272.1 [M+H]⁺.

Preparation 126 2-[tert-Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethyl] 4-methylbenzenesulfonate, Isomer 2

To a solution of 2-[(tert-butyldimethylsilyl) oxy]-1-(5-fluoropyridin-2-yl) ethanol, Isomer 2 (30.4 g, 112 mmol), DMAP (1.37 g, 11.2 mmol), and Et₃N (22.7 g, 224 mmol) in DCM (0.2 L) cooled to 0° C. is added TsCl (27.8 g, 146 mmol). The reaction is stirred at 0° C. for 3 hours then stored overnight at 0° C. The resultant suspension is filtered and the insoluble material is rinsed with MTBE. H₂O (5 ml) is added to the filtrate. The filtrate is then concentrated in vacuo and the material is purified by silica gel chromatography eluting with 0% to 100% EA in heptane to afford the title compound (39.8 g, 93.5 mmol) as a white, waxy solid. ES/MS m/z 426.0 [M+H]⁺.

Preparation 127 2,2,2-Trifluoro-1-(oxan-4-yl)ethanol

TMSCF₃ (3.74 g, 26.28 mmol) and TBAF (3.50 mL, 3.50 mmol, 1 mol/L) is added dropwise at 0° C. under N₂ to a stirred solution of oxane-4-carbaldehyde (2.00 g, 17.52 mmol) in THF (20.00 mL) and the mixture is stirred for 4 hrs at RT under N₂. The reaction is quenched by the addition of MeOH (5 mL), and the mixture is dried under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (4:1) to give the title compound as a yellow solid (3.1 g, 96.07%). ¹H NMR (300 MHz, d₆-DMSO) δ 6.16 (d, 1H), 3.93-3.81 (m, 2H), 3.81-3.68 (m, 1H), 3.39-3.20 (m, 2H), 1.92-1.72 (m, 1H), 1.60 (d, 1H), 1.56-1.35 (m, 3H).

Preparation 128 2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 1 and 2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 2

To a stirred solution of 2-iodopyridine (10.0 g, 48.78 mmol) in THF (150.0 mL) is added a soln of n-BuLi (21.4 mL, 53.65 mmol, 2.5M) in hexanes dropwise at −75° C. under N₂. The resulting mixture is stirred at −75° C. for 1 hr. To the above mixture is added pivaldehyde (5.0 g, 58.51 mmol) dropwise over a 10-minute period. After being stirred at −75° C. for 1 hr, the reaction is allowed to warm to RT then is quenched with H₂O (100.0 mL). The mixture is extracted with EtOAc (3×200 mL). The combined organic layers are dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 15:1) to afford the title compound as a white solid (2.6 g, 32%). ES/MS m/z 166.3 [M+H]⁺.

Separation of the 2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol (1.1 g, 6.7 mmol) enantiomers is performed using the following conditions: Column: CHIRALCEL AY-H, 2*25 cm, Sum; eluting with 5% EtOH in Hex (10 mM NH₃ in MeOH); 260/216 nm; to afford 2,2-dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 1 as a light-yellow solid (400 mg, 36%). t_((R))=5.3 min. and 2,2-dimethyl-1-(pyridin-2-yl)propan-1-ol, Isomer 2 as a white solid (440 mg, 40%). t_((R))=6.2 min. Analytical column used for Rt: CHIRALCEL AY-3, 4.6*50 cm; eluting with 5% EtOH in hexanes; 254 nm.

Preparation 129 1-(2-Pyridyl)propyl acetate, Isomer 2

To a stirred solution of 1-(pyridin-2-yl)propan-1-ol (2.00 g, 14.58 mmol) and Ac₂O (2.98 g, 29.16 mmol) in DCM (10.00 mL) is added TEA (4.43 g, 43.74 mmol) at RT under a N₂. The reaction is stirred overnight, quenched with H₂O (20 mL), and extracted with DCM (2×20 mL). The combined organic layers are washed with brine (2×10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 50% ACN in water; UV 254 nm to afford a brown oil (2.50 g, 95.7%). ES/MS m/z 180.3.

The brown oil (1.00 g, 5.58 mmol) is subjected to the following conditions: Column: CHIRALPAK IG, 20*250 mm, 5 μm; eluting with 15% EtOH in CO₂; 203 nm; to afford and 1-(pyridin-2-yl)propyl acetate, Isomer 2 (400 mg), t_((R)) is 3.86 min with ee=100%; ES/MS m/z 180.3 [M+H]⁺.

The following compound is prepared essentially as described for 1-(2-pyridyl)propyl acetate, Isomer 1 using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

TABLE 13 Prep ES/MS m/z t_((R)) No. Chemical Name Structure [M + H]⁺ min 130¹ [2-Methoxy-1-(2- pyridyl)ethyl] acetate, Isomer 1

196.2 3.27 ¹Column: CHIRALPAK IG, 2 * 25 cm, 5 μm; eluting with 15% EtOH in CO₂, 254 nm.

Preparation 131 1-(2-Pyridyl)propan-1-ol, Isomer 2

To 1-(pyridin-2-yl)propyl acetate, Isomer 2 (380 mg, 2.12 mmol) in MeOH (3.00 mL) and H₂O (3.00 mL) is added LiOH (101.55 mg, 4.24 mmol) in portions at RT under N₂. The reaction is stirred for 1 hr. The reaction is diluted with H₂O (20 mL), then extracted with EtOAc (2×20 mL). The combined organic layers are washed with brine (2×10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to afford the title compound as a light-yellow oil (260 mg, 90%). ES/MS m/z 138.1 [M+H]⁺.

The following compound is prepared essentially as described for 1-(2-pyridyl)propan-1-ol, Isomer 2 using the appropriate reagents and adjusting the reaction time to determine completion of the reaction.

TABLE 14 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 132 2-Methoxy-1-(2- pyridyl)ethanol, Isomer 1

154.1

Preparation 133 1-[2-(2-Methoxyethylamino)-5-(trifluoromethyl)-3-pyridyl]ethanol

A solution of 1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)ethan-1-ol (0.200 g, 0.89 mmol), 2-methoxyethan-1-amine (200 mg, 2.66 mmol), and DIPEA (573 mg, 4.43 mmol) in i-PrOH (4 mL) is stirred for 18 hr at 100° C. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with a linear gradient of 0% to 30% MeOH in DCM to afford the title compound (30 mg, 13%) as a brown oil. ES/MS m/z 265.1 [M+H]⁺.

Preparation 134 (1S)-1-[4-(2,2,2-Trifluoroethyl)-1,2,4-triazol-3-yl]ethanol

A mixture of (2S)—N′-[(1E)-(dimethylamino)methylidene]-2-hydroxypropane hydrazide (3.0 g, 18.8 mmol), ACN (10.0 mL) and HOAc (2.26 g, 37.7 mmol) is heated at 90° C. under N₂. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is taken on to the next step without further purification. ES/MS m/z 196.1 [M+H]⁺.

Preparation 135 (1S)-1-(5-Fluoropyridin-2-yl)ethyl methanesulfonate

To a stirred solution of (1S)-1-(5-fluoropyridin-2-yl)ethanol (500.0 mg, 3.54 mmol) and TEA (1.07 g, 10.63 mmol) in DCM (10.0 mL) is added dropwise MsCl (608.69 mg, 5.313 mmol) at RT under N₂. The reaction is stirred for 1 hr at RT, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers are washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound as a light-yellow oil (740 mg, 95.2%). ES/MS m/z 220.0 [M+H]⁺.

Preparation 136 [2,2,2-Trifluoro-1-(5-fluoro-2-pyridyl)ethyl] trifluoromethanesulfonate

To 2,2,2-trifluoro-1-(5-fluoropyridin-2-yl)ethanol (700.00 mg, 3.59 mmol) and TEA (1.09 g, 10.76 mmol) in DCM (5.00 mL) is added Tf₂O (2.02 g, 7.17 mmol) dropwise at 0° C. under N₂. The resulting mixture is stirred for 3 hr at RT, diluted with water (5 mL) and separated. The aq. layer is extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo to give the title compound as a crude product (1 g) which is carried forward without a further purification. ES/MS m/z 328.0 [M+H]⁺.

Preparation 137 2,2,2-Trifluoro-1-(oxan-4-yl)ethyl trifluoromethanesulfonate

Tf₂O (766.02 mg, 2.715 mmol) is added dropwise to stirred solution of 2,2,2-trifluoro-1-(oxan-4-yl)ethanol (500.00 mg, 2.72 mmol) and DIEA (1052.71 mg, 8.14 mmol) in DCM (10.00 mL) at 0° C. under N₂. The mixture is stirred for 1 hr at RT under N₂ and then used directly without further purification.

The following compounds are prepared essentially as described for 2,2,2-trifluoro-1-(oxan-4-yl)ethyl trifluoromethanesulfonate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from −70° C. to 0° C.

TABLE 15 Prep No. Chemical Name Structure 138 tert-Butyl (3S)-3- (trifluoromethanesulfonyloxy)pyrrolidine- 1-carboxylate

139 tert-Butyl (2S,4S)-2-methyl-4- (trifluoromethanesulfonyloxy)pyrrolidine- 1-carboxylate

140 tert-Butyl (2R,4S)-2-methyl-4- (trifluoromethanesulfonyloxy)pyrrolidine- 1-carboxylate

141 tert-Butyl (3R)-3- (trifluoromethylsulfonyloxy)pyrrolidine- 1-carboxylate

Preparation 142 tert-Butyl 4-(methane sulfonyl oxy)-2,2-dimethylpyrrolidine-1-carboxylate

TEA (940.02 mg, 9.29 mmol) is added dropwise to a stirred mixture of tert-butyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (800.00 mg, 3.72 mmol) in DCM (10.00 mL) at RT under N₂. MsCl (553.35 mg, 4.83 mmol) is added dropwise to the solution over 2 min at 0° C., and the mixture is stirred for 2 hrs at RT. The reaction is quenched with H₂O (150 mL) and the mixture is extracted with DCM (2×200 mL). The combined organic extracts are washed with brine (2×150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a brown-yellow solid (1.1 g, crude), which is used directly without further purification. ¹H NM/R (400 MHz, d₆-DMSO) δ 5.23-5.18 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.45 (m, 1H), 3.22 (s, 3H), 2.40-2.14 (m, 2H), 1.41 (s, 9H), 1.23 (d, 3H).

The following compounds are prepared essentially as described for tert-butyl 4-(methanesulfonyl oxy)-2,2-dimethylpyrrolidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 16 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 143 tert-Butyl (2S,4S)-4- (methanesulfonyloxy)- 2-methylpyrrolidine- 1-carboxylate

a 144 tert-Butyl (2R,4R)-4- (methanesulfonyloxy)- 2-methylpyrrolidine- 1-carboxylate

280.3 145 tert-Butyl (2S,4R)-4- (methanesulfonyloxy)- 2-methylpyrrolidine- 1-carboxylate

b 146 tert-Butyl (2R,4S)-4- (methanesulfonyloxy)- 2-methylpyrrolidine- 1-carboxylate

c 147 [(1S)-1-[4-(2,2,2- Trifluoroethyl)-1,2,4- triazol-3-yl]ethyl] methanesulfonate

274.0 a¹H NMR (400 MHz, CDCl₃) δ 5.21-5.15 (m, 1H), 4.05-3.80 (m, 2H), 3.56 (dd, 1H), 3.03 (s, 3H), 2.51-2.40 (m, 1H), 1.90-1.81 (m, 1H), 1.47 (s, 9H), 1.28 (d, 3H). b¹H NMR (400 MHz, d₆-DMSO) δ 5.23-5.18 (m, 1H), 3.94-3.84 (m, 1H), 3.66-3.60 (m, 1H), 3.51-3.45 (m, 1H), 3.22 (s, 3H), 2.46-2.34 (m, 1H), 1.93-1.83 (m, 1H), 1.41 (s, 9H), 1.23 (d, 3H). c¹H NMR (300 MHz, d₆-DMSO) δ 5.23-5.19 (m, 1H), 3.5-3.80 (m, 1H), 3.63 (dd, 1H), 3.48 (dt, 1H), 3.24 (s, 3H), 2.49-2.34 (m, 1H), 1.87 (d, 1H), 1.41 (s, 9H), 1.23 (d, 3H).

Preparation 148 2-(1-Bromoethyl)-N,N-dimethyl-benzamide

2-ethyl-N,N-dimethylbenzamide (0.81 g, 4.6 mmol), AIBN (75 mg, 0.46 mmol) and NBS (0.89 g, 5.0 mmol) are added into a vial that is evacuated and backfilled with N₂ (3×). CCl₄ (5 mL) is added and the reaction mixture is stirred at 80° C. for 2 hr. Upon cooling to RT, the reaction is filtered, and the solids are rinsed with CCl₄ (2×10 mL). The filtrate is concentrated to obtain the title compound as a clear oil (0.8 g, 70%), which is carried forward without further purification.

Preparation 149 tert-Butyl 4-(2-tert-butoxycarbonylhydrazino)-3,3-difluoro-piperidine-1-carboxylate

A mixture of tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (10.00 g, 42.51 mmol), tert-butoxycarbohydrazide (3.09 g, 23.38 mmol) and AcOH (2.55 g, 42.51 mmol) in MeOH (40 mL) is stirred for 30 min at 50° C. under N₂. Upon cooling to RT NaBH₃CN (8.01 g, 127.53 mmol) is added in portions. The reaction is stirred for 2 hr at 50° C. The mixture is basified to pH 8 with sat. aq. NaHCO₃. The mixture is extracted with EtOAc (3×150 mL), organic layers combined and washed with brine (3×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1) to afford the title compound as an off-white oil (5 g, 67%). ES/MS m/z 240.2 [M+H—C8H16]⁺.

Preparation 150 3,3-Difluoro-4-(5-methylpyrazol-1-yl)piperidine

A mixture tert-butyl 4-[[(tert-butoxycarbonyl)amino]amino]-3,3-difluoropiperidine-1-carboxylate (5.50 g, 15.7 mmol) and 4,4-dimethoxybutan-2-one (3.10 g, 23.5 mmol) in AcOH (100 mL) is stirred overnight at 50° C. under N₂. To the above mixture is added HBr (25 mL) at RT. The reaction is stirred overnight. No brominated product is detected by LCMS. The mixture is concentrated in vacuo. The residue is carried forward to the next step without a further purification. ES/MS m/z 202.3 [M+H]⁺.

Preparation 151 tert-Butyl 3,3-difluoro-4-(5-methylpyrazol-1-yl)piperidine-1-carboxylate

To 3,3-difluoro-4-(5-methyl-1H-pyrazol-1-yl)piperidine (5.50 g, 27.33 mmol) and TEA (27.66 g, 273.3 mmol) in DCM (100 mL) is added Boc₂O (29.83 g, 136.67 mmol) at RT under N₂. The reaction is stirred 2 hr then concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (20:1 to 10:1) to give crude product. The crude product is purified by reverse phase chromatography with the following conditions: column, C18; mobile phase, eluting with 40% to 60% ACN in water (0.1% FA) to afford the title compound as a yellow oil (3 g, 36.4%). ES/MS m/z 302.3 [M+H]⁺.

Preparation 152 tert-Butyl 4-[3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

To methyl 2-(5-methyl-1H-pyrazol-3-yl)acetate (6 g, 38.92 mmol) and Cs₂CO₃ (25.36 g, 77.83 mmol) in DMF (80 mL) at RT is added tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (16.31 g, 58.39 mmol). The reaction is stirred for 3 hr at 60° C. under N₂. Upon cooling to RT, the reaction is poured into H₂O (400 mL), extracted with EtOAc (3×500 mL), organic layers are combined and washed with brine (3×200 mL), dried over Na₂SO₄, filtered, and rinsed with EtOAc (3×80 mL). The filtrate is concentrated in vacuo and the residue is purified by Prep-HPLC using the following conditions: Column: HEXI SpringXB-C18, 50*250, 10 um; eluting with a gradient of 30% to 55% ACN in H₂O (0.05% TFA), flow rate: 100 mL/min; to afford the title compound (420 mg, 3.20%) as a yellow oil. ES/MS m/z 338.3 [M+H]⁺.

Preparation 153 tert-Butyl 4-(5-bromo-4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate

A solution of tert-butyl 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazine-1-carboxylate (538 mg, 2.01 mmol) and NBS (430 mg, 2.41 mmol) in MeOH (5 mL) is heated to 40° C. for 20 minutes. Upon cooling to RT the reaction is extracted with 3:1 (v/v) chloroform:iPrOH. Organic phase is washed with 10% Na₂S₂O₃, H₂O, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to a yellow oil. The oil is purified by silica gel chromatography eluting with 5 to 20% MeOH in DCM to afford the title compound as a colorless oil (620 mg, 89.0%). ES/MS m/z 246.1, 248.8 (⁷⁹Br/⁸¹Br) [M+2H-Boc]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-(5-bromo-4-methyl-1,2,4-triazol-3-yl)piperazine-1-carboxylate using the appropriate reagents and solvents and adjusting the reaction times to determine completion of the reactions.

TABLE 17 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 154^(1,2) tert-Butyl 4-(4- bromo-5-methyl- pyrazol-1-yl)-3,3- difluoro- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 379.7/381.7 155   tert-Butyl 4-[4- bromo-3-(2- methoxy-2-oxo- ethyl)-5-methyl- pyrazol-1- yl]piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 416.1/418.1 ¹DCM used as solvent ²Purified by silica gel column chromatography, eluting with DCM:MeOH (30:1 to 15:1).

Preparation 156

A solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (4.00 g) in DCM (20 mL) is basified to pH-10 with DIEA (3 mL) then cooled to −60° C. under N₂. tert-Butyl (3R)-3-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate is added dropwise and the reaction is stirred for 4 hr at −60° C. The mixture is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: column, C18; eluting with 20% to 30% ACN in H₂O (0.1% FA), 220 nm. To afford the title compound as a light-yellow solid (7.00 g). ES/MS m/z (⁷⁹Br/⁸¹Br) 385.1/387.1 [M+H]⁺.

Preparation 157 tert-Butyl (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

Cs₂CO₃ (19.20 g, 58.941 mmol) is added in portions to a stirred RT mixture of 4-bromopyrazole (2.89 g, 19.65 mmol) and tert-butyl (1R,3s,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.00 g, 19.65 mmol) in DMF (50 ml) and the mixture is stirred overnight at 70° C. under N₂. The mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1-5:1) to give a crude product (5.2 g). The crude product is repurified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 80% ACN in H₂O (0.1% FA), 220 nm to give the title compound as an off-white solid (3.5 g, 47.5%). ES/MS m/z 341.1/343.1 [M+H-tBu+ACN]⁺.

The following compounds are prepared essentially as described for tert-butyl (1R,3r,5S)-3-(4-bromo-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. K₂CO₃ can also be used as the base. Temperature is varied from 70° C. to 80° C.

TABLE 18 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 158¹ tert-Butyl (3R)-3-(4- bromopyrazol-1- yl)pyrrolidine-1- carboxylate

a 159² tert-Butyl (3S)-3-(4- bromopyrazol-1- yl)pyrrolidine-1- carboxylate

b 160³ tert-Butyl (2S,4R)-4- (4-bromopyrazol-1- yl)-2- methylpyrrolidine-1- carboxylate

c 161⁴ tert-Butyl (2R,4S)-4- (4-bromopyrazol-1- yl)-2- methylpyrrolidine-1- carboxylate

330.1/ 332.1 162⁴ tert-Butyl (2S,4S)-4- (4-bromopyrazol-1- yl)-2- methylpyrrolidine-1- carboxylate

330.1/ 332.1 163⁵ tert-Butyl 4-(4- bromopyrazol-1-yl)- 2,2- dimethylpyrrolidine- 1-carboxylate

344.1/ 346.1 164⁴ tert-Butyl (2R,4R)-4- (4-bromopyrazol-1- yl)-2- methylpyrrolidine-1- carboxylate

d ¹The mixture is filtered, the filter cake is washed with EtOAc (3 × 20 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc. ²Crude product is not repurified. ³The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; mobile phase, ACN in H₂O (0.1% NH₄HCO₃). Not repurified. ⁴The mixture is filtered, the filter cake is washed with DCM (2 × 10 mL), and the filtrate is concentrated under reduced pressure prior to purification by reverse Combi-flash chromatography. ⁵Purified with only reverse Combi-flash chromatography. a¹H NMR (300 MHz, d₆-DMSO) δ 8.08 (s, 1H), 7.59 (s, 1H), 4.97-4.89 (m, 1H), 3.73-3.65 (m, 1H), 3.57-3.51 (m, 1H), 3.46-3.37 (m, 2H), 2.36-2.24 (m, 2H), 1.40 (d, 9H). b¹H NMR (400 MHz, CDCl₃) δ 7.55-7.50 (m, 2H), 4.89-4.83 (m, 1H), 3.77-3.51 (m, 4H), 2.38-2.33 (m, 2H), 1.48 (s, 9H). c¹H NMR (300 MHz, CDCl₃) δ 7.61 (d, 1H), 7.49 (d, 1H), 4.77-4.61 (m, 1H), 4.15-4.01 (m, 1H), 4.05-3.94 (m, 1H), 3.63 (dd, 1H), 2.71-2.55 (m, 1H), 2.25-2.10 (m, 1H), 1.49 (s, 9H), 1.31 (d, 3H). d¹H NMR (300 MHz, d₆-DMSO) δ 8.04 (s, 1H), 7.58 (s, 1H), 5.03-4.93 (m, 1H), 3.72-3.57 (m, 1H), 3.68-6.58 (m, 2H), 2.55-2.44 (m, 1H), 2.15-1.85 (m, 1H), 1.39 (s, 9H), 1.20 (d, 3H).

Preparation 165 tert-Butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

Cs₂CO₃ (18.36 g, 56.35 mmol) is added in portions at RT under N₂ to a stirred mixture of tert-butyl 2-(methanesulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylate (6.00 g, 18.78 mmol) and 4-bromopyrazole (2.76 g, 18.78 mmol) in DMF (50.00 mL) and the mixture is stirred for 2 hrs at 100° C. under N₂. The mixture is cooled to RT, diluted with H₂O (100 mL), and extracted with EtOAc (3×150 mL). The combined organic layers are washed with brine (2×200 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18 eluting with a gradient of 40% to 50% ACN in H₂O (0.1% FA), 220 nm, to give the title compound (5 g). The product is dissolved in DCM (100 mL), washed with brine (2×150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as an off-white solid (4.5 g, 64.7%). ¹H NMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 7.45 (s, 1H), 4.80-4.69 (m, 1H), 3.47-3.38 (m, 2H), 3.38-3.29 (m, 2H), 2.51-2.38 (m, 2H), 2.38-2.25 (m, 2H), 1.69-1.61 (m, 4H), 1.47 (s, 9H).

The following compounds are prepared essentially as described for tert-butyl 2-(4-bromopyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Temperature is varied from 70° C. to 100° C.

TABLE 19 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 166  tert-Butyl (1R,3s,5S)-3- (4-bromo-1H-pyrazol-1- yl)-8- azabicyclo[3.2.1]octane- 8-carboxylate

b 167¹ tert-Butyl (4R)-4-(4- bromopyrazol-1- yl)azepane-1- carboxylate

c 168  tert-Butyl (4S)-4-(4- bromopyrazol-1- yl)azepane-1- carboxylate

344.1/346.1 169² tert-Butyl 3-(4-bromo- 3-methylpyrazol-1- yl)azetidine-1- carboxylate

301.1/303.1 170³ tert-Butyl 4-(4-bromo- 3-methylpyrazol-1- yl)piperidine-1- carboxylate

344.1/346.1 ¹The mixture is filtered, the filter cake is washed with DCM (3 × 20 mL) the filtrate is concentrated under reduced pressure, and the residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; 40-60% ACN in H₂O. ²The crude product is used directly without further purification. ³The mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography eluting with (6:1-1:1 PE/EtOAc. ^(a 1)H NMR (300 MHz, CDCl₃) δ 7.51 (d, 2H), 4.28-4.18 (m, 2H), 4.00-3.89 (m, 1H), 3.35-3.25 (m, 1H), 3.05-2.95 (m, 1H), 2.35-1.93 (m, 2H), 1.67-1.56 (m, 2H), 1.48 (s, 9H). b¹H NMR (400 MHz, d₆-DMSO) δ 7.98 (s, 1H), 7.54 (s, 1H), 4.82-4.64 (m, 1H), 4.23-4.09 (m, 2H), 2.04-1.82 (m, 6H), 1.81-1.72 (m, 2H), 1.42 (s, 9H) c¹H NMR (300 MHz, CDCl₃) δ 7.46 (d, 1H), 7.43 (d, 1H), 4.25 (ddt, 1H), 3.75-3.20 (m, 4H), 2.35-1.84 (m, 6H), 1.50 (s, 9H)

Preparation 171 tert-Butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate

A stirred solution of tert-butyl 3-(4-bromopyrazol-1-yl)azetidine-1-carboxylate (7.50 g, 24.82 mmol) in THF (160 mL) at 0° C. under N₂ is treated with LDA (2 mmol/L in THF) (37 mL, 74.46 mmol) and the mixture is stirred for 30 min. CH₃I (10.57 g, 74.46 mmol) is added and the mixture is stirred for 2 hrs at RT under N₂. The reaction is quenched with H₂O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (1×100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (9:1-5:1) to give the title compound as a yellow solid (4.13 g, 52.62%), which is used directly without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.53 (s, 1H), 5.04-4.93 (m, 1H), 4.48-4.40 (m, 2H), 4.36-4.28 (m, 2H), 2.27 (s, 3H), 1.48 (s, 9H).

The following compounds are prepared essentially as described for tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions and adjusting the purification system as appropriate. Temperature is varied from −78° C. to RT. The reaction can also be quenched with NH₄Cl.

TABLE 20 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺  172¹ tert-Butyl (3R)-3-(4- Bromo-5- methylpyrazol-1- yl)pyrrolidine-1- carboxylate

a  173¹ tert-Butyl (3S)-3-(4- bromo-5- methylpyrazol-1- yl)pyrrolidine-1- carboxylate

b 174 tert-Butyl 2-(4-bromo- 5-methylpyrazol-1-yl)- 7-azaspiro[3.5]nonane- 7-carboxylate

c 175 tert-Butyl (3R)-3-(4- bromo-5- methylpyrazol-1- yl)piperidine-1- carboxylate

344.1/346.1 176 tert-Butyl (3S)-3-(4- bromo-5- methylpyrazol-1- yl)piperidine-1- carboxylate

d 177 tert-Butyl (1R,3r,5S)-3- (4-bromo-5-methyl-1H- pyrazol-1-yl)-8- azabicyclo[3.2.1]octane- 8-carboxylate

370.2/372.2 178 tert-Butyl (1R,3s,5S)-3- (4-bromo-5-methyl-1H- pyrazol-1-yl)-8- azabicyclo[3.2.1]octane- 8-carboxylate

370.2/372.2  179¹ tert-Butyl (4R)-4-(4- bromo-5- methylpyrazol-1- yl)azepane-1- carboxylate

e 180 tert-Butyl (4S)-4-(4- bromo-5- methylpyrazol-1- yl)azepane-1- carboxylate

358.1/360.1 181 tert-Butyl (2S,4R)-4-(4- bromo-5- methylpyrazol-1-yl)-2- methylpyrrolidine-1- carboxylate

f  182¹ tert-Butyl (2R,4S)-4-(4- bromo-5- methylpyrazol-1-yl)-2- methylpyrrolidine-1- carboxylate

344.09/346.09  183¹ tert-Butyl (2S,4S)-4-(4- bromo-5- methylpyrazol-1-yl)-2- methylpyrrolidine-1- carboxylate

344.1/346.1  184¹ tert-Butyl 4-(4-bromo- 5-methylpyrazol-1-yl)- 2,2- dimethylpyrrolidine-1- carboxylate

358.1/360.1  185² tert-Butyl (2R,4R)-4-(4- bromo-5- methylpyrazol-1-yl)-2- methylpyrrolidine-1- carboxylate

g ¹Crude product used directly without further purification. ²Dried extract is filtered and the filtrate is concentrated under reduced pressure. a¹H NMR (300 MHz, d₆-DMSO) δ 7.53 (s, 1H), 5.00 (d, 1H), 3.67 (d, 1H), 3.50-3.42 (m, 2H), 2.27 (s, 3H), 2.24-2.10 (m, 2H), 1.40 (d, 9H). b¹H NMR (400 MHz, d₆-DMSO) δ 7.53 (d, 1H), 5.00 (s, 1H), 3.71-3.65 (m, 1H), 3.54-3.42 (m, 3H), 2.27 (s, 3H), 2.19-2.06 (m, 2H), 1.41-1.39 (m, 9H). c¹H NMR (300 MHz, d₆-DMSO) δ 7.53 (s, 1H), 4.91-4.86 (m, 1H), 3.33-3.18 (m, 4H), 2.40-2.14 (m, 7H), 1.64-1.59 (m, 2H), 1.52-1.47 (m, 2H), 1.40 (s, 9H). d¹H NMR (300 MHz, CDCl₃) δ 7.42 (d, 1H), 4.05-3.95 (m, 1H), 3.20-3.00 (m, 1H), 2.77-2.68 (m, 1H), 2.29 (s, 3H), 2.20-2.10 (m, 3H), 2.07-2.04 (m, 1H), 1.89-1.82 (m, 1H), 1.67-1.57 (m, 1H), 1.45 (s, 9H). e¹H NMR (400 MHz, CDCl₃) δ 7.35 (s, 1H), 4.05-3.99 (m, 1H), 3.75-3.10 (m, 4H), 2.19 (s, 3H), 2.18-1.81 (m, 6H), 1.41 (s, 9H). f¹H NMR (400 MHz, CDCl₃) δ 7.44 (s, 1H), 4.64-4.54 (m, 1H), 3.98-3.90 (m, 2H), 3.62-3.45 (m, 1H), 2.54-2.45 (m, 1H), 2.35-2.21 (m, 4H), 1.48 (s, 9H), 1.37 (d, 3H). g¹H NMR (300 MHz, d₆-DMSO) δ 7.51 (s, 1H), 5.09-4.94 (m, 1H), 4.11-3.95 (m, 1H), 3.70-3.60 (m, 1H), 3.52 (dd, 1H), 2.50-2.40 (m, 1H), 2.28 (s, 3H), 2.02-1.91 (m, 1H), 1.39 (s, 9H), 1.22 (d, 3H).

Preparation 186 1-(Azetidin-3-yl)-4-bromo-5-methylpyrazole

A solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate (3.00 g, 9.488 mmol) in TFA (10 mL) and DCM (20 mL) is stirred for 2 hrs at RT. The solution is concentrated under reduced pressure to give the title compound as a brown oil (4 g, crude, TFA salt), which is used directly without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 5.16-5.06 (m, 1H), 4.30 (t, 2H), 3.88 (t, 2H), 2.25 (s, 3H). The compound is used directly without further purification.

The following compound is prepared essentially as described for 1-(Azetidin-3-yl)-4-bromo-5-methylpyrazole using the appropriate reagents, and adjusting the reaction time to determine completion of the reaction.

TABLE 21 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 187 4-(4-Bromo-5- methyl- triazol-1- yl)piperidine HCl

(⁷⁹Br/⁸¹Br) 245.1/ 247.1

Preparation 188 tert-Butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate

Tf₂O (3.62 g, 12.82 mmol) is added dropwise to a stirred mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (2.00 g, 10.68 mmol) and DIEA (4.14 g, 32.05 mmol) in DCM (30 mL) at −40° C. under N₂. The mixture is added dropwise to a stirred solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (4 g, crude) in DCM (30 mL). The mixture is made basic to pH-10 with DIEA (3 mL) at −40° C. under N₂. The mixture is stirred for an additional 4 hrs at −40° C. and then concentrated under vacuum. The solution is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 20% to 30% ACN in H₂O (0.1% FA); 220 nm to give the title compound as a light-yellow solid (500 mg, 12%). ES/MS m/z (⁷⁹Br/⁸¹Br) 385.1/387.1 [M+H]⁺.

Preparation 189 tert-Butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate

tert-Butyl (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (2.05 g, 6.41 mmol, crude) is added dropwise to a stirred solution of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (3 g, 13.88 mmol, crude) in DCM (30 mL). The solution is made basic to pH-10 with DIEA (3 mL) at −40° C. under N₂ and the mixture is stirred for 4 hrs at −40° C. The solution is quenched by H₂O (30 mL) and extracted with DCM (2×100 mL). The combined organic extracts are washed with brine (2×80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 30% to 50% ACN in H₂O (0.1% FA) to give the title compound as a light-yellow oil (520 mg, 38.5%). ES/MS m/z (⁷⁹Br/⁸¹Br) 385.0/387.0 [M+H]⁺.

The following compound is prepared essentially as described for tert-butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from −70° C. to −40° C.

TABLE 22 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 190¹ tert-Butyl (2R,4R)-4-[3-(4-[3- cyano-4-methoxypyrazolo[1,5- a]pyridin-6-yl]-5-methylpyrazol- 1-yl)azetidin-1-yl]-2- methylpyrrolidine-1-carboxylate

492.3 ¹Prep TLC (EtOAc).

Preparation 191 tert-Butyl 3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate

NaBH₃CN (2.18 g, 34.709 mmol) is added in portions to a stirred mixture of 1-(azetidin-3-yl)-4-bromo-5-methylpyrazole (5.00 g, 23.14 mmol) and tert-butyl 3-oxopiperidine-1-carboxylate (5.53 g, 27.77 mmol) in MeOH (50 mL) at RT and the mixture is stirred for 2 hrs. The reaction is quenched with H₂O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (5:1˜1:1) to give the title compound as a brown solid (4.0 g, 43.2%). ES/MS m/z (⁷⁹Br/⁸¹Br) 399.1/401.1 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Temperature is varied from RT to 50° C.

TABLE 23 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 192¹ tert-Butyl 4-[3-(4- bromo-5- methylpyrazol-1- yl)azetidin-1-yl]-3,3- difluoropiperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 435.1/437.1 193² tert-Butyl 3-[3-[4-(3- cyano-4-methoxy- pyrazolo[1,5-a]pyridin- 6-yl)-5-methyl-pyrazol- 1-yl]azetidin-1-yl]-6- azabicyclo[3.2.1]octane- 6-carboxylate

518.4 ¹TFA and catalytic AcOH is added to the initial solution before NaBH₃CN is added. ²Purified by silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1)

Preparation 194 tert-Butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate

Preparation 195 tert-Butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate

tert-Butyl-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carboxylate (1.0 g) is separated by Prep-chiral with the following conditions: Column, Phenomenex Lux 5μ Cellulose-4, AXIA Packed, 2.12*25 cm, 5 μm; eluting with 20% MeOH in CO₂, flow rate 40 mL/min; 210 nm; Analytical LC conditions are: Column Lux Cellulose-4, 0.46*10 cm, 3.0 μm eluting with 10% to 50% MeOH (0.1% DEA) in CO₂, flow rate of 2 mL/min to give t_((R)) tert-butyl (3S)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-yl]piperidine-1-carboxylate, t_((R)) is 1.85 min with 100% ee as a light-yellow solid (460 mg); t_((R)) tert-butyl (3R)-3-[3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-yl]piperidine-1-carboxylate is 2.18 min with 100% ee as a light-yellow solid (450 mg). ES/MS m/z 399.1/401.1 [M+H]⁺.

Preparation 196 tert-Butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl (3R,4S)-4-azido-3-fluoro-piperidine-1-carboxylate (1.00 g, 4.09 mmol) and trimethyl(prop-1-yn-1-yl)silane (1.38 g, 12.28 mmol) is irradiated with microwave radiation for 1 hr at 150° C. The reaction is concentrated in vacuo to afford the title compound (1.5 g) as a white solid, which is used in the next step without further purification. ES/MS m/z 357.1 [M+H]⁺

The following compounds are prepared essentially as described for tert-butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 24 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 197   tert-Butyl (3S,4S)-3- fluoro-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

357.2 198   tert-Butyl (3S,4R)-3- fluoro-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

357.2 199   tert-Butyl (3R,4R)-3- fluoro-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

357.2 200^(1,2) (1r,3r)-3-(5-methyl-4- (trimethylsilyl)-1H-1,2,3- triazol-1-yl)cyclobutan-1-ol

a 201^(2,3) tert-Butyl (3S,4S)-3- hydroxy-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

355.3 [M − H]⁺ 202²   tert-Butyl (3R,4S)-3- hydroxy-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

355.2 203³   tert-Butyl (3S,4R)-3- hydroxy-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

355.2 204⁴   tert-Butyl (3R,4R)-3- hydroxy-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

355.3 205⁵   tert-butyl (3RS,4RS)-3- methyl-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

 353.15 206⁶   tert-butyl (3RS,4SR)-3- methyl-4-(5-methyl-4- trimethylsilyl-triazol-1- yl)piperidine-1- carboxylate

353.2 ¹Purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane. ²Reaction was run in toluene ³Purified by silica gel chromatography, eluting with PE:EA (4:1). ⁴Purified by silica gel chromatography, eluting with PE:EA (2:1). ⁵Purified by silica gel chromatography, eluting with PE:EA (5:1). ⁶Purified by silica gel chromatography, eluting with PE:EA (6:1 to 5:1). a¹H NMR (400 MHz, DMSO-d6) δ 0.26 (s, 9H) 2.24 (s, 3H) 2.36-2.47 (m, 2H) 2.65-2.75 (m, 2H) 4.42-4.59 (m, 1H) 4.97 (ttd, J = 8.38, 8.38, 5.14, 5.14, 0.73 Hz, 1H) 5.31 (d, J = 4.89 Hz, 1H).

Preparation 207 tert-Butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate

K₂CO₃ (414.00 mg, 3.00 mmol) is added in portions to a stirred solution of tert-butyl 4-azidopiperidine-1-carboxylate (226.00 mg, 1.00 mmol) and EAA (130.00 mg, 1.20 mmol) in DMSO (5.00 mL) at RT under N₂. The mixture is stirred for 6 hrs at 80° C. under N₂. The mixture is cooled to RT, H₂O (10 mL) is added, and the mixture is extracted with EtOAc (3×30 mL). The combined organic extracts are washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1 to 0:1) to give the title compound as a yellow oil (330 mg, 66.80). ES/MS m/z 339.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. DMF can also be used as the solvent. Temperature is varied from RT to 80° C.

TABLE 25 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 208  Ethyl 1-[1-(tert- butoxycarbonyl)azetidin-3-yl]- 5-methyl-1,2,3-triazole-4- carboxylate

311.2 209¹ Ethyl 1-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3- yl]-5-methyl-1,2,3-triazole-4- carboxylate

325.3 210¹ Ethyl 1-[(3S)-1-(tert- butoxycarbonyl)pyrrolidin-3- yl]-5-methyl-1,2,3-triazole-4- carboxylate

325.1 211  tert-Butyl 2-(4-ethoxycarbonyl- 5-methyl-triazol-1-yl)-7- azaspiro[3.5]nonane-7- carboxylate

a 212  tert-Butyl 4-(4-ethoxycarbonyl- 5-methyl-triazol-1-yl)azepane- 1-carboxylate

353.2 213² tert-Butyl (3S)-3-(4- ethoxycarbonyl-5-methyl- triazol-1-yl)piperidine-1- carboxylate

339.3 214  tert-Butyl 4-(4-ethoxycarbonyl- 5-methyl-triazol-1-yl)azepane- 1-carboxylate

353.2 215³ tert-Butyl (3R)-3-(4- ethoxycarbonyl-5-methyl- triazol-1-yl)piperidine-1- carboxylate

339.1   216^(4,2) Cis-Ethyl 1-(3- benzyloxycyclobutyl)-5- methyl-triazole-4-carboxylate

b 217  tert-Butyl 4-[2-(4- ethoxycarbonyl-5-methyl- triazol-1-yl)-1,1-dimethyl- ethyl]piperazine-1-carboxylate

396.4 218⁶ tert-Butyl (2SR,4RS)-2- cyclopropyl-4-(4- ethoxycarbonyl-5-methyl- triazol-1-yl)piperidine-1- carboxylate

379.3 ¹The mixture is filtered, the filter cake is washed with DCM (3 × 50 mL), and the filtrate is concentrated under reduced pressure. ²Purified by silica gel column chromatography, eluting with PE:EtOAc (1:1). ³Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 2:1). ⁴DMF used as solvent. ⁵Purified by silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1). ⁶Reverse flash chromatography: Column, C18, 55% to 60% ACN in H₂O (0.1% NH₄HCO₃). a¹H NMR (400 MHz, CDCl₃) δ 4.86-4.73 (m, 1H), 4.49-4.38 (m, 2H), 3.47-3.40 (m, 2H), 3.38-3.30 (m, 2H), 2.67-2.58 (m, 2H), 2.57-2.47 (m, 5H), 1.76-1.64 (m, 4H), 1.46 (s, 9H), 1.44-1.39 (m, 3H). b¹H NMR (300 MHz, DMSO-d6) δ 7.43-7.25 (m, 5H), 5.22-4.99 (m, 1H), 4.50-4.37 (m, 3H), 4.30 (q, 2H), 2.88-2.75 (m, 2H), 2.70-2.58 (m, 2H), 2.47 (s, 3H), 1.30 (t, 3H).

Preparation 219 1-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic Acid

A solution of tert-butyl 4-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate (300.00 mg, 0.890 mmol) and KOH (100.00 mg, 1.780 mmol) in H₂O (5.00 mL) is stirred for 2 hrs at 50° C. under N₂. The mixture is acidified to a pH of 4 with HCl (aq.) (1N) at 0° C. and extracted with EtOAc (3×30 mL). The combined organic extracts are washed with brine (2×15 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (250 mg, 900%). ES/MS m/z 311.3 [M+H]⁺.

The following compounds are prepared essentially as described for 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. The solvent can be DMSO and the base can be NaOH.

TABLE 26 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 220 1-[1-(tert- Butoxycarbonyl)azetidin-3- yl]-5-methyl-1,2,3-triazole- 4-carboxylic acid

283.1 221 1-[(3R)-1-(tert- Butoxycarbonyl)pyrrolidin- 3-yl]-5-methyl-1,2,3- triazole-4-carboxylic acid

297.2  222¹ 1-[(3S)-1-(tert- Butoxycarbonyl)pyrrolidin- 3-yl]-5-methyl-1,2,3- triazole-4-carboxylic acid

241.0 223 1-(1-tert- Butoxycarbonylazepan-4- yl)-5-methyl-triazole-4- carboxylic acid

325.2 224 1-[(3S)-1-tert- Butoxycarbonyl-3- piperidyl]-5-methyl- triazole-4-carboxylic acid

311.3 225 1-[(3R)-1-tert- Butoxycarbonyl-3- piperidyl]-5-methyl- triazole-4-carboxylic acid

311.2 226 Cis-1-(3-Benzyloxy cyclobutyl)-5-methyl- triazole-4-carboxylic acid

288.3 227 1-[2-(4-tert- Butoxycarbonylpiperazin- 1-yl)-2-methyl-propyl]-5- methyl-triazole-4- carboxylic acid

368.3 228 1-[(2SR,4RS)-1-tert- butoxycarbonyl-2- cyclopropyl-4-piperidyl]-5- methyl-triazole-4- carboxylic acid

351.2 ¹Precipitated solids are collected by filtration, washed with H₂O (3 × 20 mL), and dried in vacuo.

Preparation 229 tert-Butyl 4-[4-bromo-3-(2-hydroxyethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-bromo-3-(2-methoxy-2-oxo-ethyl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (390 mg, 0.94 mmol) in MeOH (5 mL) is added LiBH₄ (24.49 mg, 1.12 mmol) at 0° C. under N₂. The reaction is stirred 1 hr at RT, cooled to 0° C. and quenched with H₂O (10 mL). The mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, washed with brine (2×10 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo to afford the title compound (350 mg, 96.22%) as a yellow oil. ES/MS m/z (⁷⁹Br/⁸¹Br) 388.1/390.1 [M+H]⁺.

Preparation 230 7-Chloro-5-[[(1R)-1-(5-fluoro-2-pyridyl)ethyl]amino]imidazo[1,2-a]pyridine-3-carbonitrile

To 5,7-dichloroimidazo[1,2-a]pyridine-3-carbonitrile (600 mg, 2.83 mmol) and (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride (749.7 mg, 4.25 mmol) in toluene (10 mL) is added Cs₂CO₃ (5532 mg, 16.98 mmol), BINAP (176.2 mg, 0.28 mmol) and Pd(AcO)₂ (4.33 mg, 0.005 mmol) at RT under N₂. The reaction is stirred for 2 hr at 100° C. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (5:1 to 1:3), to afford the title compound as a yellow solid (250 mg, 28%). ES/MS m/z 316.1 [M+H]⁺.

Preparation 231 7-Chloro-5-methoxyimidazo[1,2-a]pyridine

A solution of 4-chloro-6-methoxypyridin-2-amine (7.00 g, 44.14 mmol), chloroacetaldehyde (8.32 g, 52.99 mmol, 50%) and NaHCO₃ (11.12 g, 132.42 mmol) in n-butanol (140.00 mL) is divided into fourteen batches and stirred overnight at 65° C. in sealed tubes. The solution is cooled to RT, diluted with H₂O (200 mL) and extracted with EtOAc (3×200 mL). The organic extracts are dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product is purified by silica gel chromatography (PE:EtOAc 1:1) to give the title compound as a light-brown solid (6.1 g, 75.68%). ES/MS m/z 183.10 [M+H]⁺.

The following compound is prepared essentially as described for 7-Chloro-5-methoxyimidazo[1,2-a]pyridine using the appropriate reagents and adjusting the reaction time to determine completion of the reactions.

TABLE 27 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 232 6-Bromo-3-fluoro- pyrazolo[1,5-a] pyridin-4-ol

(⁷⁹Br/⁸¹Br) 231.0/233.0

Preparation 233 7-Chloroimidazo[1,2-a]pyridin-5-ol

A mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (2.00 g, 10.95 mmol), NaOH (50% in H₂O) (1.31 g, 16.43 mmol) and NDM (3.33 g, 16.43 mmol) in DMA (10.00 mL) is stirred for 2 hrs at 50° C. under N₂. The mixture is diluted with H₂O (100 mL), acidified to pH 4-5 with 1 M HCl to give precipitated solids that are collected by filtration and washed with PE (3×100 mL), H₂O (3×10 mL), and dried in vacuo to give the title compound as a light-yellow solid (1.5 g, 81.24%). ES/MS m/z 169.2 [M+H]⁺.

Preparation 234 tert-Butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane

To 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (6.53 g, 24.06 mmol) in THF (50.00 mL) is added 60% NaH (0.96 g, 24.06 mmol) at 0° C. under N₂. After being stirred at 0° C. for 0.5 hr, 5,7-dichloroimidazo[1,2-a]pyridine (3 g, 16.04 mmol) is added to the mixture. The reaction is stirred at RT for 2 hr under N₂. The reaction is quenched with H₂O (50 mL) then extracted with EtOAc (2×50 mL). The combined organic layers are washed with brine (2×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (5:1 to 4:1) to afford the title compound as a brown solid (2.5 g, 36.93%). ES/MS m/z 422.2. [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane using the appropriate reagents and adjusting the reaction time to determine completion of the reactions.

TABLE 28 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 235¹ 7-Chloro-5-[(5-fluoro-2- pyridyl)-(1- methoxycyclopropyl)methoxy] imidazo [1,2-a]pyridine-3-carbonitrile

373.1 236² [2-(6-Bromo-3-fluoro- pyrazolo[1,5-a]pyridin-4- yl)oxy-2-(5-fluoro-2- pyridyl)ethoxy]-tert-butyl- dimethyl-silane

(⁷⁹Br/⁸¹Br) 484.1/486.1 ¹Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1 to 5:1). ²Purified by reverse phase chromatography: Column, C18; eluting with 0% to 100% ACN in H2O (0.1% NH₃•H₂O).

Preparation 237 6-Bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (2.00 g, 8.40 mmol), (1S)-1-(pyridin-2-yl)ethanol (1.14 g, 9.24 mmol) and PPh₃ (2.64 g, 10.08 mmol) in THF (20.0 mL) is stirred for 10 min at RT under N₂. DEAD (1.76 g, 10.08 mmol) is added dropwise to the mixture over 10 min at RT. After the mixture is stirred for an additional 2 hrs at RT, it is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (PE-3:1) to give the title compound as a green oil (1.48 g, 51.3%). ES/MS m/z 343.0/345.0 [M+H]⁺.

The following compounds are prepared essentially as described for 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 0° C. to RT.

TABLE 29 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 238 6-Bromo-4-[(1S)-1-(pyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

343.0/345.0 239 7-Chloro-5-[(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridine

274.0 240 6-Bromo-4-[(1R)-1- cyclobutylethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

320.1/322.1 241 6-Bromo-4-[(1R)-1- cyclopropylethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

a 242 6-Bromo-4-[(1R)-1- phenylethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

341.8/343.8 243 7-Chloro-5-[(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridine

292.0  244¹ [2-(6-Bromopyrazolo[1,5- a]pyridin-4-yl)oxy-2-(5-fluoro- 2-pyridyl)ethoxy]-tert-butyl- dimethyl-silane, Isomer 2

468.0 ¹Purified by silica gel chromatography, eluting with PE:EtOAc (15:1 to 10:1). a¹H NMR (300 MHz, CDCl₃) δ 8.32 (d, 1H), 8.15 (s, 1H), 6.75 (d, 1H), 4.22-4.12 (m, 1H), 1.53 (d, 3H), 1.35-1.27 (m, 1H), 0.75-0.60 (m, 2H), 0.60-0.36 (m, 2H).

Preparation 245 tert-Butyl (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate

To tert-butyl (3R,4S)-3-fluoro-4-(5-methyl-4-trimethylsilyl-triazol-1-yl)piperidine-1-carboxylate (1.5 g) and SiO₂ (505.58 mg, 8.41 mmol) in ACN (15 mL) is added NBS (2.00 g, 11.22 mmol) at RT under N₂. The reaction is stirred for 2 hr at 80° C. Upon cooling to RT, the reaction is quenched with H₂O. The suspension is filtered and washed with EtOAc (2×5 mL). The filtrate is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE:EA (3:1) to afford the title compound (1.3 g, 85.1%) as a white solid. ES/MS m/z (⁷⁹Br/⁸¹Br) 363.0/365.0 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl (3R,4S)-4-(4-bromo-5-methyl-triazol-1-yl)-3-fluoro-piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 30 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 246¹ tert-Butyl (3S,4S)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-fluoro- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 363.0/365.0 247² tert-Butyl (3S,4R)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-fluoro- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 404.0/406.0 [M + H + ACN]⁺ 248¹ tert-Butyl (3R,4R)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-fluoro- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 363.1/364.9 249³ (1r,3r)-3-(4,5- dimethyl-1H-1,2,3- triazol-1- yl)cyclobutan-1-ol

a 250¹ tert-Butyl (3S,4S)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-hydroxy- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 361.08/363.0  251¹ tert-Butyl (3R,4S)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-hydroxy- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 361.08/363.0 252¹ tert-Butyl (3S,4R)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-hydroxy- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 361.1/363.1 253⁴ tert-butyl (3R,4R)- 4-(4-bromo-5- methyl-triazol-1- yl)-3-hydroxy- piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 361.1/363.1 254⁴ tert-butyl (3RS,4RS)-4-(4- bromo-5-methyl- triazol-1-yl)-3- methyl-piperidine- 1-carboxylate

(⁷⁹Br/⁸¹Br) 359.1/361.1 255⁵ tert-butyl (3RS,4SR)-4-(4- bromo-5-methyl- trazol-1-yl)-3- methyl-piperidine- 1-carboxylate

(⁷⁹Br/⁸¹Br) 359.1, 361.1 ¹Purified by silica gel chromatography, eluting with PE:EA (4:1). ²Purified by silica gel chromatography, eluting with PE:EA (3:1). ³Purified by silica gel chromatography eluting with 0% to 100% EA in heptane. ⁴Purified by silica gel chromatography, eluting with PE:EA (5:1). ⁵Purified by silica gel chromatography, eluting with PE:EA (5:1 to 4:1). a¹H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H) 2.37-2.47 (m, 2H) 2.69-2.77 (m, 2H) 4.41-4.49 (m, 1H) 4.99-5.09 (m, 1H) 5.09-5.67 (m, 1H).

Preparation 256 tert-Butyl 2-(4-bromo-5-methyl-triazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

To tert-butyl 2-[4-(ethoxycarbonyl)-5-methyl-1,2,3-triazol-1-yl]-7-azaspiro[3.5]nonane-7-carboxylate (11.1 g, 29.3 mmol.) in H₂O (100 mL) is added KOH (6.59 g, 117.3 mmol) at RT under N₂. The reaction is stirred for 2 hr at 50° C. The reaction mixture is used in the next step directly without further purification.

To 1-(7-tert-butoxycarbonyl-7-azaspiro[3.5]nonan-2-yl)-5-methyl-triazole-4-carboxylic acid is added Br₂ (6.95 g, 43.99 mmol) dropwise at RT under N₂. The reaction is stirred for 1 hr at RT then extracted with EtOAc (2×100 mL). The combined organic layers are washed with sat. Na₂S₂O₃ (100 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated to afford the title compound as a white solid (8.7 g, 75.35%). ¹H NMR (400 MHz, CDCl₃) δ 4.84-4.69 (m, 1H), 3.50-3.40 (m, 2H), 3.38-3.30 (m, 2H), 2.62-2.54 (m, 2H), 2.53-2.44 (m, 2H), 2.24 (s, 3H), 1.77-1.62 (m, 4H), 1.46 (s, 9H).

Preparation 257 tert-Butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

Br₂ (154.00 mg, 0.96 mmol) is added in portions to a stirred solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-5-methyl-1,2,3-triazole-4-carboxylic acid (248 mg, 0.80 mmol) and KOH (54.00 mg, 0.96 mmol) in H₂O (6 mL) and the mixture is stirred for 3 hrs at RT under N₂. A precipitate results, and the mixture is extracted with EtOAc (3×30 mL). The combined organic extracts are washed with brine (2×15 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow solid (190 mg, 690%). ES/MS m/z (⁷⁹Br/⁸¹Br) 345.2/347.2 [M+H]⁺, which is used directly without further purification.

The following compounds are prepared essentially as described for tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 0° C. to RT. HBr/AcOH can be used as the solvent.

TABLE 31 ES/MS m/z Prep (⁷⁹Br/⁸¹Br) No. Chemical Name Structure [M + H]⁺ 258 tert-Butyl 3-(4-bromo- 5-methyl-1,2,3-triazol- 1-yl)azetidine-1- carboxylate

317.1/ 319.1 259 tert-Butyl (3R)-3-(4- bromo-5-methyl-1,2,3- triazol-1- yl)pyrrolidine-1- carboxylate

331.0/ 333.0 260 tert-Butyl (3S)-3-(4- bromo-5-methyl-1,2,3- triazol-1- yl)pyrrolidine-1- carboxylate

331.1/ 333.1 261¹ tert-Butyl 4-(4-bromo- 5-methyl-triazol-1- yl)azepane-1- carboxylate

359.1/ 361.1 262 tert-Butyl (3S)-3-(4- bromo-5-methyl- triazol-1-yl)piperidine- 1-carboxylate

345.2/ 347.2 263 tert-Butyl (3R)-3-(4- bromo-5-methyl- triazol-1-yl)piperidine- 1-carboxylate

345.0/ 347.0 264³ Cis-1-(3- Benzyloxycyclobutyl)- 4-bromo-5-methyl- triazole

a 265⁴ tert-Butyl 4-[2-(4- bromo-5-methyl- triazol-1-yl)-1,1- dimethyl-ethyl]-3-oxo- piperazine-1- carboxylate

415.8/ 417.8 266⁵ tert-Butyl (2SR,4RS)- 4-(4-bromo-5-methyl- triazol-1-yl)-2- cyclopropyl-piperidine- 1-carboxylate

385.1/ 387.1 ¹Reverse flash chromatography: Column, C18, 10% to 50% ACN in H₂O (0.1% NH₄HCO₃). ²Silica gel column chromatography eluting with PE:EtOAc (5:1). ³Reverse flash chromatography: Column, C18, 50% to 80% ACN in H₂O (0.1% FA). ⁴Reverse flash chromatography: Column, C18, 40% to 70% ACN in H₂O (0.1% FA). ⁵Reverse flash chromatography: Column, C18, 50% to 55% ACN in H₂O (0.1% NH₄HCO₃). a¹H NMR (400 MHz, DMSO-d6) δ 7.40-7.34 (m, 4H), 7.33-7.27 (m, 1H), 5.14-5.06 (m, 1H), 4.45 (s, 2H), 4.42-4.34 (m, 1H), 2.81-2.72 (m, 2H), 2.66-2.56 (m, 2H), 2.22 (s, 3H).

Preparation 267 tert-Butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]piperazine-1-carboxylate

To tert-butyl 4-[2-(4-bromo-5-methyl-triazol-1-yl)-1,1-dimethyl-ethyl]-3-oxo-piperazine-1-carboxylate (1 g, 2.40 mmol) in THF (10.00 mL) is added BH₃ (12.01 mL, 12.01 mol, 1M in THF) dropwise at 0° C. under N₂. The reaction is stirred for 2 hr at RT, cooled to 0° C. and quenched with MeOH (10 mL). The mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with PE:EtOAc (4:1 to 2:1) to afford the title compound (0.53 g, 54.8%) as a light yellow oil. ES/MS m/z (⁷⁹Br/⁸¹Br) 401.8/403.8 [M+H]⁺.

Preparation 268 Cis-3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanol

A mixture of 1-(3-benzyloxycyclobutyl)-4-bromo-5-methyl-triazole (8.5 g, 26.38 mmol) and FeCl₃ (8.56 g, 52.76 mmol) in DCM (100 mL) is stirred for 2 hr at 50° C. under N₂. Upon cooling to RT the reaction is diluted with H₂O (50 mL). The mixture is extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×100 mL), dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuo to afford the title compound (8.00 g, crude) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 5.09-4.99 (m, 1H), 4.55-4.42 (m, 1H), 2.80-2.71 (m, 2H), 2.48-2.37 (m, 2H), 2.21 (s, 3H).

Preparation 269 3-(4-Bromo-5-methyl-triazol-1-yl)cyclobutanone

A mixture of 3-(4-bromo-5-methyl-triazol-1-yl)cyclobutanol (4.00 g, 17.23 mmol) and Dess-Martin (10.97 g, 25.85 mmol) in DCM (40 mL) is stirred for 2 hr RT under N₂. The mixture is diluted with H₂O (100 mL), extracted with EtOAc (3×100 mL), washed with brine (2×100 mL), dried over Na₂SO₄ and filtered. The filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: column, C18; mobile phase, 20% to 40% ACN in H₂O (0.1% FA) to afford the title compound (2.10 g, 52.96%) as a white solid. ES/MS m/z (⁷⁹Br/⁸¹Br) 229.9/231.9 [M+H]⁺.

Preparation 270 1-Bromo-3-[(diphenylmethyl)amino]-3-methylbutan-2-one

A mixture of 3-[(diphenylmethyl)amino]-3-methylbutan-2-one (700.00 mg, 2.62 mmol) and Br₂ (418.39 mg, 2.62 mmol) in HBr in AcOH (40%, 6.00 mL) is stirred for 2 hrs at RT under N₂. The reaction is quenched with NaHCO₃/ice (300 mL) at 0° C. The mixture is extracted with DCM (2×300 mL). The combined organic extracts are washed with brine (1×300 mL), dried over anhydrous Na₂SO₄, filtered and the filtrate is concentrated under reduced pressure to give the title compound (800 mg) as yellow solid which is used without further purification. ES/MS m/z (⁷⁹Br/⁸¹Br) 346.0/348.0 [M+H]⁺.

Preparation 271 1-(Diphenylmethyl)-2,2-dimethylazetidin-3-one

A mixture of 1-bromo-3-[(diphenylmethyl)amino]-3-methylbutan-2-one (2.10 g, 6.07 mmol) and NaHCO₃ (764.21 mg, 9.10 mmol) in DMF (6.00 mL) and H₂O (1.50 mL) is stirred for 12 hours at RT under N₂. The mixture is diluted with EtOAc (100 mL) and washed with H₂O (3×80 mL). The organic layer is washed with brine (2×80 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 24% to 27% ACN in H₂O to give the title compound as a yellow solid (1.30 g, 75.4%). ES/MS m/z 284.3 [M+H₂O+H]⁺.

Preparation 272 6-(1-[1-[1-(Diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (300.00 mg, 0.89 mmol), 1-(phenylmethyl)-2,2-dimethylazetidin-3-one (473.29 mg, 1.78 mmol), AcOH (5.36 mg, 0.089 mmol) and NaBH₃CN (140.11 mg, 2.23 mmol) in MeOH (4.00 mL) is stirred for 12 hours at 50° C. under N₂. The reaction is quenched with NaHCO₃ (50 mL) at RT and the aqueous layer is extracted with EtOAc (2×80 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 38% to 40% ACN in H₂O (0.1% FA) to give the title compound as a yellow solid (400 mg, 76.57%). ES/MS m/z 586.3 [M+H]⁺.

The following compounds are prepared essentially as described for 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The reaction can also be quenched with H₂O, and the filtrate can be washed with EtOAc.

TABLE 32 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 273 tert-Butyl 4-[3-(4-[3- cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-2,2- dimethylpyrrolidine- 1-carboxylate

506.4 274¹ Cis-tert-Butyl 4-[3- (4-bromo-5-methyl- triazol-1-yl) cyclobutyl] piperazine-1- carboxylate

(⁷⁹Br/⁸¹Br) 400.0/402.0 ¹Purified by silica gel column chromatography, eluting with 1% to 50% EA in PE.

Preparation 275 tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 1 and Preparation 276 tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate, Isomer 2

The isomers of tert-Butyl 4-[3-(4-bromo-5-methylpyrazol-1-yl)azetidin-1-yl]-3,3-difluoropiperidine-1-carboxylate (1.9 g) are isolated by Chiral Prep-HPLC with the following conditions: Column, N-CHIRALPAK IG (Lot No. IG30CS-VL001), 4.6*100 mm, 3.0 μm; eluting with a gradient of 10%-50% MeOH (20 mM NH₃); flow rate: 2 mL/min; 210 nm; t_((R)) Isomer 1 is 2.30 min with 100% ee as a white solid (810 mg, 42.63%); t_((R)) Isomer 2 is 2.52 min with 100% ee as a white solid (788 mg, 41.47%).

Preparation 277 6,6-Difluoro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one

F-TEDA (23.95 g, 67.61 mmol) is added in portions to a stirred solution of 5H,6H-cyclopenta[b]pyridin-7-one (3.00 g, 22.53 mmol) and Na₂SO₄ (16.00 g, 112.64 mmol) in ACN (30 mL) at RT under N₂, and the mixture is stirred for 3 hrs at 80° C. under N₂. The mixture is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE/EtOAc (3:1) to give the title compound as a light-yellow solid (2.2 g, 57.73%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.88 (dd, 1H), 8.14 (dd, 1H), 7.78 (dd, 1H), 3.75 (t, 2H).

Preparation 278 6,6-Difluoro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

A stirred solution of 6,6-difluoro-3H,4H,5H-cyclopenta[b]pyridin-7-one (1 g, 5.84 mmol) in MeOH (10 mL) is treated with NaBH₄ (220 mg, 5.82 mmol) and stirred for 2 hrs at RT under N₂. The mixture is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of PE/EtOAc (3:1) to give the title compound as a white solid (800 mg, 80%). ES/MS m/z 172.0 [M+H]⁺.

Preparation 279 (R)-2,2,2-Trifluoro-1-(pyridin-2-yl)ethyl trifluoromethanesulfonate

Tf₂O (597.33 mg, 2.12 mmol) is added dropwise at 0° C. to a stirred solution of (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethanol (250 mg, 1.41 mmol) and TEA (428.47 mg, 4.23 mmol) in DCM (10 mL) and the mixture is stirred for 4 hrs at RT under N₂. The mixture is diluted with H₂O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts are washed with brine (1×20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a yellow oil (280 mg, crude). The product is used directly without further purification. ES/MS m/z 309.8 [M+H]⁺.

The following compound is prepared essentially as described for (R)-2,2,2-trifluoro-1-(pyridin-2-yl)ethyl trifluoromethanesulfonate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 33 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 280¹ 6,6-Difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl trifluoromethanesulfonate

304.0 ¹The extracts are concentrated under vacuum, and are not washed with brine, dried over anhydrous Na₂SO₄, or filtered.

Preparation 281 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

To 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (5.00 g, 22.02 mmol) and bis(pinacolato)diboron (6710.27 mg, 26.43 mmol) in dioxane (10 mL) are added KOAc (6.48 g, 66.06 mmol) and Pd(dppf)Cl₂ (322.25 mg, 0.44 mmol, 0.02 equiv.) at RT under N₂. The resulting mixture is stirred for 2 hr at 80° C. under N₂. The mixture is carried forward without a further purification. ES/MS m/z 275.1 [M+H]⁺.

Preparation 282 [5-[2-[tert-Butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]boronic Acid

A mixture of tert-Butyl-[2-(7-chloroimidazo[1,2-a]pyridin-5-yl)oxy-2-(5-fluoro-2-pyridyl)ethoxy]-dimethyl-silane (1.8 g, 4.27 mmol), bis(pinacolato)diboron (1.62 g, 6.40 mmol), KOAc (1.05 g, 10.67 mmol) and XPhos (0.24 g, 0.51 mmol), Pd₂(dba)₃ (0.39 g, 0.427 mmol) in dioxane (20 mL) is stirred at 80° C. for 2 hr under N₂. Upon cooling to RT, the reaction is carried forward to the next step without a further purification. ES/MS m/z 432.1 [M+H]⁺.

Preparation 283 5-Methoxyimidazo[1,2-a]pyridin-7-ylboronic Acid

A stirred mixture of 7-chloro-5-methoxyimidazo[1,2-a]pyridine (1.00 g, 5.48 mmol) and bis(pinacolato)diboron (1.67 g, 6.57 mmol) in 1,4-dioxane is treated with KOAc (1.61 g, 16.43 mmol) and Xphos Pd G4 (0.05 g, 0.06 mmol) at RT under N₂ and stirred for 8 hrs at 80° C. The mixture is diluted with H₂O (100 mL), acidified to pH 4 with HCl aq. (1 N), and extracted with i-PrOH:CHCl₃ (3:1)(3×200 mL). The combined organic extracts are dried over anhydrous Na₂SO₄ and concentrated under vacuum to give the title compound as a light-pink solid (1.4 g, crude). ES/MS m/z 193.0 [M+H]⁺.

The following compounds are prepared essentially as described for 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. The catalyst can also be XPhos Pd G4.

TABLE 34 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 284 3-Cyano-5-[(1R)-1- (pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-ylboronic acid

308.9 285 [5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]imidazo [1,2-a]pyridin-7-yl] boronic acid

302.0 286¹ (5-Methoxy-3-methyl- imidazo[1,2-a]pyridin-7- yl)boronic acid

207.1 ¹0.1 eq Xantphos Pd G4 and 0.2 eq X-Phos used

Preparation 287 4-[(1R)-1-(Pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A stirred RT solution of 6-bromo-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (1.40 g, 4.08 mmol), KOAc (1.20 g, 12.24 mmol) and bis(pinacolato)diboron (1.24 g, 4.90 mmol) in dioxane (20.00 mL) under N₂ is treated with Pd(dppf)Cl₂—CH₂Cl₂ (0.17 g, 0.20 mmol), and the mixture is stirred for 2 hrs at 100° C. under N₂. The mixture is filtered, the filter cake is washed with EtOAc (3×20 mL), and the filtrate is concentrated under reduced pressure to give the title compound as a black solid (2.5 g, crude), which is used directly without further purification. ES/MS m/z 391.3 [M+H]⁺.

The following compounds are prepared essentially as described for 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80° C. to 100° C. The base can also be KF. The catalyst can also be Pd(PPh₃)₄, Pd₂(dba)₃ or Pd(dppf)Cl₂ and can be used alone or in combination with XPhos Pd G4.

TABLE 35 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 288 4-[(1S)-1-(Pyridin-2- yl)ethoxy]-6-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

309.1 289¹ 5-[(1R)-1-(Pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-ylboronic acid

284.3 290² 4-[(1R)-1- Cyclobutylethoxy]-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

368.2 291¹ 4-[(1R)-1- Cyclopropylethoxy]-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

354.2 292¹ 4-[(1R)-1- Phenylethoxy]-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

390.2 293³ 4-Isopropoxy-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan- 2-yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

246.0 294⁴ (3-Cyano-5-methoxy- imidazo[1,2-a]pyridin- 7-yl)boronic acid

218.0 295⁵ 4-Methoxy-6- (4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

300.2 296¹ [3-Cyano-5-[(5-fluoro- 2-pyridyl)-(1- methoxycyclopropyl) methoxy]imidazo[1,2- a]pyridin-7-yl]boronic acid

383.0 297 [3-Cyano-5-[[(1R)-1- (5-fluoro-2- pyridyl)ethyl]amino] imidazo[1,2-a]pyridin- 7-yl]boronic acid

326.1 298 3-Fluoro-4-methoxy- 6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine

293.2 299 4-Methoxy-6-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazolo[1,5- a]pyridine

275.2 300 tert-Butyl-[2-(5- fluoro-2-pyridyl)-2-[6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)pyrazolo[1,5- a]pyridin-4-yl]oxy- ethoxy]-dimethyl- silane, Isomer 2

514.3 301 tert-Butyl-[2-(5- fluoro-2-pyridyl)-2-[3- fluoro-6-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2- yl)pyrazolo[1,5- a]pyridin-4-yl]oxy- ethoxy]-dimethyl- silane, Isomer 2

532.4 ¹Mixture is used directly without further purification. ²Mixture is filtered, washed with 1,4-dioxane, concentrated under reduced pressure, and used directly without further purification. ³The reaction mixture is filtered and purified with reverse phase C18 chromatography. ⁴Upon workup the organic layers are combined, washed with H₂O. The aqueous layer is acidified to pH 3-4 with conc. HCl. The precipitate is collected by filtration, washed with water, and dried in vacuo. ⁵Purified by silica gel column chromatography, eluting with PE/EtOAc (20:1 to 3:1). ^(a)Material is used without further purification.

Preparation 302 3-Chloro-4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine

A mixture of 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5.06 g, 18.46 mmol) and NCS (2.47 g, 18.46 mmol) in CHCl₃ (5 mL) is heated at 50° C. for 1 hr. Upon cooling to RT, the reaction is washed with H₂O, sat. aq. NaHCO₃, brine, dried over Na₂SO₄ and filtered. The filtrate is concentrated to afford the title compound (5.79 g, 18 mmol) as a light brown solid. ES/MS m/z 227.0 [M+H-C6H12]⁺.

Preparation 303 tert-Butyl 4-[4-(5-chloroimidazo[1,2-a]pyridin-7-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

To 7-bromo-5-chloroimidazo[1,2-a]pyridine (700.0 mg, 3.02 mmol) and tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (946.7 mg, 2.41 mmol) in dioxane/H₂O (4:1, 10.0 mL) is added Pd(PPh₃)₄ (349.4 mg, 0.30 mmol) and KF (527.0 mg, 9.07 mmol) at RT under N₂. The reaction is stirred for 2 hr at 100° C. under N₂. The resulting mixture is filtered, the filter cake is washed with EtOAc (3×100 mL). The filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (1:2) to afford the title compound as a yellow solid (700 mg, 55.6%). ES/MS m/z 416.2 [M+H]⁺.

Preparation 304 tert-Butyl 4-[5-methyl-4-(5-oxo-6H-imidazo[1,2-c]pyrimidin-7-yl)pyrazol-1-yl]piperidine-1-carboxylate

7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one (300 mg, 1.77 mmol), tert-butyl 4-(5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.04 g, 2.65 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (127 mg, 0.27 mmol), and K₃PO₄ (1.13 g, 5.31 mmol) in 1,4-dioxane (4 mL) is treated with Pd₂(dba)₃ (243 mg, 0.27 mmol) and sparged with N₂ for 5 min. The reaction is sealed and refluxed overnight. Upon cooling to RT, the reaction is diluted with H₂O and extracted with EtOAc (3×). The combined organic layers are washed with H₂O, followed by brine, dried over Na₂SO₄, filtered, and concentrated to a yellow oil. The oil is dissolved into DCM and purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM to afford the title compound (470 mg, 1.18 mmol, 66.7%) as a solid. ES/MS m/z 399.2 [M+H]⁺.

Preparation 305 tert-Butyl 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (1.60 g, 4.63 mmol), 5-methoxyimidazo[1,2-a]pyridin-7-ylboronic acid (1.33 g, crude), K₂CO₃ (1.92 g, 13.90 mmol), Pd(PPh₃)₄ (0.27 g, 0.23 mmol), dioxane (8 mL) and H₂O (2.00 mL) is stirred for 8 hrs at 90° C. under N₂. The mixture is cooled to RT, diluted with EtOAc (100 mL), washed with H₂O (50 mL), and then brine (80 mL). The combined organic layers are dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1 to 1:1) to give the title compound as a brown solid (520 mg, 18.2%). ES/MS m/z 413.3 [M+H]⁺.

Preparation 306 tert-Butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To 4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (5 g, 18.24 mmol) and tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (6.93 g, 20.06 mmol) in dioxane (80 mL) and water (20 mL) is added K₂CO₃ (7.56 g, 54.72 mmol) and Pd(DtBPF)Cl₂ (0.24 g, 0.36 mmol) RT under N₂. The reaction is stirred overnight at 80° C. Upon cooling to RT, the resultant mixture is diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (2×80 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with a gradient of 30% to 60% EtOAc in PE to afford the title compound as a light-brown solid (4.5 g, 59.8%). ES/MS m/z 413.2 [M+H]⁺.

Preparation 307 tert-butyl 4-[4-(3-chloro-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A solution of tert-butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (16.1 g, 39.02 mmol) in CHCl₃ (50 mL) is treated with PPTS (981 mg, 3.90 mmol) followed by NCS (5.21 g, 39.02 mmol). The reaction is stirred at 40° C. for 95 min. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by phase silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford the title compound (17.7 g, 101%) as a colorless solid. ES/MS m/z 391.2 [M+2H-tBu]⁺.

Preparation 308 tert-Butyl 3-[5-methyl-4-[5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]triazol-1-yl]azetidine-1-carboxylate

To 5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (1.00 g, 3.53 mmol), tert-butyl 3-(4-bromo-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate (1.23 g, 3.89 mmol) and K₂CO₃ (1.46 g, 10.60 mmol) in dioxane (8.00 mL) and H₂O (2.00 mL) is added Pd(PPh₃)₄ (0.41 g, 0.35 mmol) at RT under N₂. The resulting mixture is stirred at 100° C. for 2 hr under N₂. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with a gradient of 5% to 10% MeOH in DCM to afford the title compound as a yellow solid (550 mg, 32.74%). ES/MS m/z 476.1 [M+H]⁺.

Preparation 309 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A mixture of 5-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (1.6 g, 3.71 mmol), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (1.41 g, 4.08 mmol), K₂CO₃ (1.54 g, 11.13 mmol), Pd(DtBPF)Cl₂ (242 mg, 0.37 mmol) in dioxane (20 mL) and H₂O (5 mL) is stirred at 80° C. for 2 hr under N₂. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE:EtOAc (1:2 to 1:1) to afford the title compound as a brown solid (1.2 g, 49.63%). ES/MS m/z 652.4 [M+H]⁺.

Preparation 310 tert-Butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a] yridine-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carboxylate

A stirred solution of tert-butyl 3-(4-bromo-5-methylpyrazol-1-yl)azetidine-1-carboxylate (2.50 g, 7.91 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (2.37 g, 7.91 mmol) in dioxane:H₂O (80 mL:20 mL) is treated with K₂CO₃ (3.28 g, 23.72 mmol) and Pd(PPh₃)₄ (0.09 g, 0.08 mmol) at RT under N₂, and the mixture is stirred overnight at 100° C. under N₂. The mixture is cooled to RT, the reaction is quenched with H₂O (100 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts are washed with brine (1×150 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (10:1-1:1) to give the title compound as a white solid (1.88 g, 58.21%). ¹H NMR (300 MHz, d₆-DMSO) δ 8.61-8.51 (m, 2H), 7.95 (s, 1H), 7.09 (d, 1H), 5.41-5.26 (m, 1H), 4.37-4.26 (m, 2H), 4.18 (d, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.43 (s, 9H).

The following compounds are prepared essentially as described for tert-butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a] yridine-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80° C. to 100′C. The solvent can also be toluene:H₂O. The base can also be KOAc, K₃PO₄, or KF. The catalyst can also be CsF, Pd(AcO)₂, PCy₃, Pd(dppf)Cl₂ DCM, Pd₂(dba)₃·CHCl₃ or Pd(dppf)Cl₂, alone or in combination with X-Phos or Xphos Pd G4. Alternatively, the reaction can be carried out without a catalyst. The mixture can also be extracted with PE and CHCl₃:i-PrOH.

TABLE 36 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 311 tert-Butyl (3R)-3-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)pyrrolidine-1- carboxylate

423.2 312 tert-Butyl (3S)-3-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1-yl) pyrrolidine-1- carboxylate

423.1 313 tert-Butyl 3-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)azetidine-1- carboxylate

410.3 314¹ tert-Butyl 4-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carboxylate

438.2 315 tert-Butyl 4-(4- [3-cyano-4- isopropoxypyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-1,2,3- triazol-1- yl)piperidine-1- carboxylate

466.3 316 tert-Butyl (3R)-3-(4- [3-cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carboxylate

437.3 317² tert-Butyl 3-(4-[3- cyano-4- isopropoxypyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-1,2,3- triazol-1- yl)azetidine-1- carboxylate

318 tert-Butyl (3S)-3- (4-[3-cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carboxylate

437.1 319³ tert-Butyl (3R)-3- (4-(3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl)-5- methyl-1H-1,2,3- triazol-1- yl)pyrrolidine-1- carboxylate

424.3 320⁴ tert-Butyl (3S)-3-[3- (4-[3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl] pyrrolidine-1- carboxylate

478.4 321 tert-Butyl (1R,3s,5S)-3- (4-(3-cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl)-5- methyl-1H-pyrazol- 1-yl)-8-azabicyclo [3.2.1]octane-8- carboxylate

322 tert-Butyl 3-(4-[3- cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-1,2,3- triazol-1- yl)azetidine-1- carboxylate

501.4 323⁵ tert-Butyl 4-(4-[3- cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carboxylate

528.4 324⁵ tert-Butyl 3-(4-[3- cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)azetidine-1- carboxylate

500.3 325 tert-Butyl (4R)-4-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azepane-1- carboxylate

451.1 326⁶ tert-Butyl 4-(4-[3- cyano-4-[(1S)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carboxylate

528.3 327 tert-Butyl (3S)-3-[3- (4-[3-cyano-4- [(1R)-1-(pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine- 1-carboxylate

569.4 328 tert-Butyl 4-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6- yl]pyrazol-1- yl)piperidine-1- carboxylate

423.3 329 tert-Butyl (4S)-4-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azepane-1- carboxylate

451.2 330 tert-Butyl 3-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6- yl]pyrazol-1- yl)azetidine- 1-carboxylate

339.3 331 tert-Butyl 3-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-3- methylpyrazol-1- yl)azetidine-1- carboxylate

a 332 tert-Butyl 4-(4-[5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-pyrazol-1- yl)piperidine-1- carboxylate

503.2 333 tert-Butyl 4-(4-[3- cyano-4-[(1R)-1- cyclobutylethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carboxylate

506.3 334 tert-Butyl (2S,4R)- methoxypyrazolo[1, 4-(4-[3-cyano-4- 5-a]pyridin-6-yl]-5- methylpyrazol-1-yl)- 2-methylpyrrolidine- 1-carboxylate

437.3 335 tert-Butyl 4-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1-yl)- 2,2- dimethylpyrrolidine- 1-carboxylate

451.2 336² tert-Butyl (2R,4R)- 4-(4-[3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1-yl)- 2-methylpyrrolidine- 1-carboxylate

437.20 337⁷ tert-Butyl 4-[4-[3- cyano-5-[(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2- a]pyridin-7- yl]-5-methyl-triazol- 1-yl]piperidine-1- carboxylate

504.3 338 tert-Butyl 4-[3-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-3,3- difluoropiperidine- 1-carboxylate, Isomer 1

528.2 339 tert-Butyl 4-[3-(4- [3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin- 1-yl]-3,3- difluoropiperidine-

528.3 1-carboxylate, Isomer 2 340 tert-Butyl 4-(4-[3- cyano-4-[(1R)-1- cyclobutylethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carboxylate

449.2^(b) 341⁸ tert-Butyl 4-[4-(5- chloroimidazo[1,2- a]pyridin-7-yl)-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

416.2 342² tert-butyl 2-[4-[3- cyano-5-[(1R)-1- (5-fluoro-2- pyridyl)ethoxy] imidazo[1,2-a] pyridin-7-yl]-5- methyl-triazol- 1-yl]-7-azaspiro [3.5]nonane- 7-carboxylate

587.2 343⁹ tert-Butyl 4-[4-(5- methoxy-3-methyl- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

427.2 344^(10,11) tert-butyl 2-[4- (3-cyano-5-methoxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1-yl]- 7-azaspiro[3.5]nonane- 7-carboxylate

478.2 345¹³ tert-Butyl 4-[4-(3- cyano-4-methoxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-pyrazol-1- yl]-3,3-difluoro- piperidine-1- carboxylate

473.3 346¹⁴ tert-Butyl 4-[4-(4- methoxypyrazolo[1, 5-a]pyridin-6-yl)-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

412.2 347¹⁵ tert-Butyl 2-[4-[3- cyano-5-[(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2-a]pyridin- 7-yl]-5-methyl-triazol- azaspiro[3.5]nonane- 7-carboxylate

569.0 348¹³ tert-butyl 4-(4-(3-cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl)-5- methyl-1H-pyrazol- 1-yl)-3,3- difluoropiperidine- 1-carboxylate

473.3 349¹⁶ tert-Butyl (3S)-3-[3- [4-(3-cyano-4- methoxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-pyrazol-1- yl]azetidin-1- yl]pyrrolidine-1- carboxylate

478.3 350¹ tert-Butyl 3-[4-[3- cyano-5-[(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2-a] pyridin-7- yl]-5-methyl- pyrazol-1- yl]azetidine-1- carboxylate

500.1 351¹⁷ tert-Butyl 4-[4-(5- methoxyimidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]azepane-1- carboxylate

c 352¹⁸ tert-Butyl (3S)-3- [4-(3-cyano-5- methoxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

438.1 353^(10,21) tert-Butyl 4-[4-(3- cyano-5-methoxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]azepane-1- carboxylate

452.3 354^(10,19,20) tert-Butyl 4-[4-[3- cyano-5-[[(1R)- 1-(5-fluoro-2- pyridyl)ethyl]amino] imidazo[1,2- alpyridin-7-yl]-5- methyl-triazol-1- yl]piperidine-1- carboxylate

546.3 355^(10,21,18) tert-Butyl (3R)- 3-[4-(3-cyano-5- methoxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

438.3 356^(22,23) tert-Butyl 4-[4-(3- fluoro-4-methoxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

431.2 357²³ Cis-tert-Butyl 4-[3- [4-(4-methoxy pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]cyclobutyl] piperazine-1- carboxylate

468.3 358²⁴ tert-Butyl 4-[4-(3- cyano-5-methoxy- imidazo[1,2- a]pyridin-7-yl)-3-(2- hydroxyethyl)-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

481.3 359²⁵ tert-Butyl 4-[4-[4-methoxy-3- (trifluoromethyl) pyrazolo[1,5-a] pyridin- 6-yl]-5-methyl- pyrazol-1- yl]piperidine-1- carboxylate

424.8 [M + H − C4H8]⁺ 360²⁶ tert-Butyl (2SR,4RS)-2- cyclopropyl-4-[4-(5- methoxyimidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1-yl] piperidine-1- carboxylate

453.2 ¹Prep-TLC (EtOAc:PE = 1:1). ²Reverse flash chromatography with the following conditions: column, C18; ACN in H₂O (0.1% NH₄HCO₃). ³Reverse flash chromatography with the following conditions: Column, C18, ACN in H₂O (0.1% FA). ⁴Reverse flash chromatography with the following conditions: Column, C18; ACN in H₂O (0.1% NH₃H₂O). ⁵Reverse flash chromatography with the following conditions: Column, C18; ACN in H₂O. ⁶Reverse flash chromatography with the following conditions: Column, C18, H₂O (0.1% FA). ⁷Silica gel column chromatography, eluting with a gradient of DCM:MeOH. ⁸Silica gel column chromatography, eluting with PE:EtOAc (1:2) ⁹Reverse flash chromatography: Column, C18, 40% to 70% ACN in H₂O (0.1% FA). ¹⁰Catalyst: Pd(DtBPF)Cl₂. ¹¹Silica gel column chromatography, eluting with PE:EtOAc (1:1). ¹³Silica gel column chromatography, eluting with PE:EtOAc (4:1 to 1:2). ¹⁴Silica gel flash column chromatography, eluting 10% to 60% EtOAc in PE. ¹⁵Prep-TLC (EtOAc). ¹⁶Silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1). ¹⁷Reverse flash chromatography with the following conditions: column, C18; 10% to 50% ACN in H₂O (0.1% NH₄HCO₃). ¹⁸Reverse flash chromatography with the following conditions: column, C18; 50% to 60% ACN in H₂O (0.1% NH₄HCO₃). ¹⁹Silica gel column chromatography, eluting with 50% to 100% EtOAc in PE. ²⁰Silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1 to 12:1). ²¹Cs₂CO₃ used as base. ²²Pd(DtBPF)Cl₂ used as catalyst ²³Silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1). ²⁴Silica gel column chromatography, eluting with PE:EtOAc (2:1 to 1:1). ²⁵Silica gel column chromatography, eluting with 0% to 100% EtOAc in heptane. ²⁶Reverse flash chromatography with the following conditions: column, C18; 10% to 50% ACN in H₂O. a ¹H NMR (300 MHz, Methanol-d₄) δ 7.82 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 6.77 (s, 1H), 4.24 (s, 3H), 3.86 − 3.73(m, 1H), 3.65-3.37 (m, 4H), 2.62 (s, 3H), 2.09-2.01 (m, 1H), 1.94 − 1.81(m, 1H), 1.54 (s, 9H), 1.49 − 1.14 (m, 4H). ^(b)ES/MS m/z [M + 2H − tBu]⁺. c ¹H NMR (300 MHz, d₆-DMSO) δ 8.59-8.49 (m, 2H), 8.35 (s, 1H), 7.12 (d, 1H), 5.24-5.11(m, 1H), 4.38-4.28(m, 2H), 4.22-4.12 (m, 2H), 4.06 (s, 3H), 2.41 (s, 3H), 1.42 (s, 9H).

Preparation 361 tert-Butyl 4-(4-[3-cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A solution of 4-[(1R)-1-(pyridin-2-yl)ethoxy]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (500 mg, 1.28 mmol), tert-butyl 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (487 mg, 1.41 mmol), K₂CO₃ (531 mg, 3.84 mmol), Pd(PPh₃)₄ (148 mg, 0.13 mmol), H₂O (2 mL) and dioxane (8 mL) is stirred overnight at 100° C. under N₂. The mixture is diluted with H₂O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts are washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a brown solid (354 mg, 52.27%). ES/MS m/z 529.3 [M+H]⁺.

Preparation 362 tert-Butyl 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate

A stirred mixture of tert-butyl 2-(4-bromo-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate (200.00 mg, 0.52 mmol) and 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (171.24 mg, 0.57 mmol) in dioxane (4.00 mL) and H₂O (1 mL) is treated with K₂CO₃ (215.77 mg, 1.56 mmol) and Pd(PPh₃)₄ (120.27 mg, 0.10 mmol) in portions at RT under N₂. The mixture is stirred for 2 hrs at 80° C. under N₂. The mixture is cooled to RT and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (3:1 to 2:1), to give the title compound as a yellow solid (110 mg, 44.3%). ES/MS m/z 462.3 [M-tBu+ACN+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 2-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)-7-azaspiro[3.5]nonane-7-carboxylate using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. Temperature is varied from 80° C. to 100° C. Toluene:H₂O can also be used as the solvent. Pd(AcO)₂, PCy₃, XPhos Pd G2, XPhos Pd G4, or Pd(dppf)Cl₂ can also be used as the catalyst or no catalyst can be used. K₃PO₄, KF or CsF can also be used as the base. Pd(DtBPF)Cl₂ may also be used as a catalyst.

TABLE 37 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 363¹ tert-Butyl 4-[4-(3-cyano-4- isopropoxy-pyrazolo[1,5- a]pyridin-6-yl)-5-methyl- pyrazol-1-yl]piperidine- 1-carboxylate

465.3 364 tert-Butyl (1R,3r,5S)-3- (4-(3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl)-5-methyl- 1H-pyrazol-1-yl)-8- azabicyclo[3.2.1]octane- 8-carboxylate

463.1 365 tert-Butyl (3S)-3-[3-(4- [3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]piperidine-1- carboxylate

492.3 366 tert-Butyl (3R)-3-[3-(4- [3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]piperidine-1- carboxylate

392.20 367 tert-Butyl (3R)-3-[3-(4- [3-cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carboxylate

569.3 368 tert-Butyl 4-(4-[3-cyano- 4-methoxypyrazolo[1,5- a]pyridin-6-yl]-3- methylpyrazol-1- yl)piperidine-1- carboxylate

381.1 [M − tBu + H]⁺ 369 tert-Butyl (2R,4S)-4-(4- [3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)-2- , methylpyrrolidine-1- carboxylate

437.3 370 tert-Butyl (2S,4S)-4- (4-[3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)-2- methylpyrrolidine-1- carboxylate

437.3 371 tert-Butyl 4-(4-[3- cyano-4-[(1R)-1- cyclopropylethoxy] pyrazolo[1,5-a] pyridin-6-yl]-5- methyl-1,2,3-triazol-1- yl)piperidine-1- carboxylate

492.3 372 tert-Butyl 4-(4-[3-cyano- 4-[(1R)-1- cyclopropylethoxy] pyrazolo[1,5-a] pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine- 1-carboxylate

491.3 373 tert-Butyl 4- (4-[3-cyano- 4-[(1R)-1- phenylethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-1,2,3-triazol-1- yl)piperidine-1- carboxylate

528.3 374² tert-Butyl (3R)-3- (3-(4-(3-cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl)-5-methyl- 1H-pyrazol-1-yl)azetidin- 1-yl)pyrrolidine-1- carboxylate

478.3 375 tert-Butyl 3-(4-[3-cyano- 5-[(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- 1,2,3 -triazol-1-yl) azetidine-1-carboxylate

501.3 376³ tert-Butyl (3S)-3-(4-[3- cyano-4- methoxypyrazolo[1, 5-a]pyridin-6-yl]- 5-methyl- 1,2,3-triazol-1-yl) pyrrolidine-1- carboxylate

424.2 377 tert-Butyl 4-[4-[5-[(1R)- 1-(5-fluoro-2- pyridyl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-triazol-1-yl] piperidine-1-carboxylate

378⁴ tert-Butyl 4-[4-[3-cyano- 5-[(1R)-1-(3- pyridyl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-triazol-1-yl] piperidine-1-carboxylate

529.2 379⁵ tert-Butyl 4-[5-(3-cyano- 4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-4-methyl- 1,2,4-triazol-3-yl] piperazine-1-carboxylate

439.2 380⁵ tert-Butyl 4-[2-[4-[3- cyano-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-triazol-1-yl]-1,1- dimethyl-ethyl] piperazine-1-carboxylate

586.3 381⁶ tert-butyl (3R,4S)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-fluoro-piperidine-1- carboxylate, Isomer 2

670.3 382⁷ tert-Butyl (3S,4S)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-fluoro-piperidine-1- carboxylate, Isomer 2

670.3 383⁸ tert-Butyl (3S,4R)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-fluoro-piperidine-1- carboxylate, Isomer 2

670.4 384⁹ tert-Butyl (3R,4R)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-fluoro-piperidine-1- carboxylate, Isomer 2

670.4 385¹⁰ (1r,3r)-3-(4-(3-Chloro-4- methoxypyrazolo[1,5-a] pyridin-6-yl)-5-methyl- 1H-1,2,3-triazol-1- yl)cyclobutan-1-ol

334.2 386¹¹ tert-Butyl (3S,4S)-4-[4- [4-[2-[tert-butyl (dimethyl) silyl]oxy-1- (5-fluoro-2- pyridyl)ethoxy] pyrazolo [1,5-a]pyridin- 6-yl]-5-methyl-triazol-1- yl]-3-hydroxy-piperidine- 1-carboxylate, Isomer 2

668.3 387¹² tert-Butyl (3R,4S)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-hydroxy-piperidine- 1-carboxylate, Isomer 2

668.4 388¹² tert-Butyl (3S,4R)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-hydroxy-piperidine- 1-carboxylate, Isomer 2

668.3 389¹³ tert-Butyl (3R,4R)-4-[4- [4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-hydroxy-piperidine- 1-carboxylate, Isomer 2

668.4 390¹⁴ tert-Butyl (3RS,4RS)-4- [4-[4-[2-[tert-butyl (dimethyl)silyl]oxy-1-(5- fluoro-2-pyridyl) ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-3-methyl-piperidine- 1-carboxylate, Isomer 2

666.3 391⁶ tert-butyl (3RS,4SR)- 4- [4-[4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2-pyridyl) ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-methyl- piperidine-1-carboxylate, Isomer 2

666.2 392¹⁵ tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2-pyridyl) ethoxy]-3-fluoro- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]-4-methyl-piperidine- 1-carboxylate, Isomer 2

684.5 ¹ISCO Column, eluting with hexanes:EtOAc (10-100%). ²Purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1). ³Purified by silica gel column chromatography, eluting with a gradient of 0% to 10% MeOH in DCM. ⁴Purified by Prep-TLC (EA) ⁵Purified by reverse Combi-flash chromatography with the following conditions: Column, C18; ACN in H₂O (0.1% NH₄HCO₃). ⁶Purified by Prep-TLC PE:EtOAc (1:1). ⁷Purified by Prep-TLC (EA). ⁸Purified by silica gel column chromatography, eluting with PE:EtOAc (1:3). ⁹Purified by silica gel column chromatography, eluting with PE:EtOAc (2:3). ¹⁰Purified by silica gel column chromatography, eluting with a gradient of 0% to 10% MeOH in DCM. ¹¹Purified by silica gel column chromatography, eluting with PE:EA (2:3). ¹²Purified by silica gel chromatography, eluting with PE:EA (1:1 to 1:2). ¹³Purified by reverse phase chromatography: column, C18; eluting with 40% to 50% ACN in H₂O (0.1% NH₄OH). ¹⁴Purified by silica gel column chromatography, eluting with PE:EtOAc (3:1). ¹⁵Purified by silica gel column chromatography, eluting with PE:EA (2:1 to 1:1).

Preparation 393 tert-Butyl (3R)-3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate

(Trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (10 mL, 8.32 mmol) is added dropwise over 5 min to a stirred solution of 4-methoxy-6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (400.00 mg, 1.18 mmol) and DIEA (307.36 mg, 2.37 mmol) in DCM (5.00 mL) at −60° C. under N₂. The mixture is stirred for 1 hr at RT under N₂, washed with H₂O (3×20 mL), and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (9:1) to give the title compound as a brown solid (411 mg, 68.36%). ES/MS m/z 506.3 [M+H]⁺.

Preparation 394 tert-Butyl (2S,4R)-4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]-2-methylpyrrolidine-1-carboxylate

Tf₂O (420.55 mg, 1.491 mmol) is added dropwise to a stirred solution of tert-butyl (2S,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (300.00 mg, 1.491 mmol) and DIEA (577.94 mg, 4.472 mmol) in DCM (5.00 mL) at −70° C. under N₂ for 1 hr. The solution of tert-butyl (2S,4S)-2-methyl-4-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate is then added dropwise to a stirred solution of 6-[1-(azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (400.00 mg, 0.95 mmol) and DIEA (367.20 mg, 2.84 mmol) in DCM (20.00 mL) at −70° C. under N₂. The solution is stirred overnight at RT, quenched by H₂O (50 mL), and extracted with DCM (2×50 mL). The combined organic extracts are washed with brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC (EtOAc) give the title compound as a light-yellow solid (80 mg, 17.18%). ES/MS m/z 492.2 [M+H]⁺.

Preparation 395 tert-Butyl (3S)-3-(4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)piperidin-1-yl)pyrrolidine-1-carboxylate

A mixture of 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (300.00 mg, 0.89 mmol), tert-butyl (3R)-3-(methanesulfonyloxy)pyrrolidine-1-carboxylate (2.37 g, 8.92 mmol) and K₂CO₃ (369.75 mg, 2.68 mmol) in toluene (3.00 mL) is stirred for 4 hrs at 150° C. under N₂. The mixture is cooled to RT, poured into H₂O (20 mL), and extracted with DCM (2×20 mL). The combined organic extracts are washed with saturated NaCl aq. (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (95:5-90:10) to give the title compound as a light-yellow solid (260 mg, 57.66%). ES/MS m/z 506.4 [M+H]⁺.

Preparation 396 tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate

A mixture of 6-(1-[1-[1-(diphenylmethyl)-2,2-dimethylazetidin-3-yl]piperidin-4-yl]-5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (400.00 mg, 0.68 mmol), Boc₂O (447.11 mg, 2.05 mmol) and Pd(OH)₂/C (287.69 mg) in MeOH (10.00 mL) is stirred for 12 hours at RT under H₂. The mixture is filtered, the filter cake is washed with MeOH (2×30 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 30% to 33% ACN in H₂O (0.1% FA) to give the title compound as a yellow solid (260 mg, 73.27%). ES/MS m/z 520.4 [M+H]⁺.

Preparation 397 tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate, Isomer 1 and Preparation 398 tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate, Isomer 2

Isomers of tert-butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate (390.00 mg) are separated by Prep-chiral chromatography with the following conditions: Column, CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; eluting with a gradient of 30% iPrOH in hexanes (10 mM NH₃MeOH); flow rate 20 mL/min; 254/220 nm; t_((R)) Isomer 1 is 10.2 min (110 mg, 28.21%) as a yellow solid with 100% ee; t_((R)) Isomer 2 is 12.7 min (120 mg, 30.77%) as a yellow solid with 99.6% ee. ES/MS m/z 520.4 [M+H]⁺.

Preparation 399 tert-Butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]azetidine-1-carboxylate

tert-Butyl 3-oxoazetidine-1-carboxylate (101.18 mg, 0.59 mmol) in MeOH (4.00 mL) is added to 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100.00 mg, 0.30 mmol) at RT. The solution is stirred for 1 hr at 40° C. After the solution is cooled to RT, NaBH₃CN (37.14 mg, 0.591 mmol) is added and the mixture is stirred for 15 hrs at RT. The mixture is diluted with EtOAc (50 mL) and washed with H₂O (2×50 mL). The organic extract is dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18;

eluting with a gradient of 50% to 60% ACN in H₂O (0.1% FA) to give the title compound as a light-yellow solid (130 mg, 89.5%). ES/MS m/z 492.2 [M+H]⁺.

Preparation 400 tert-Butyl (3R)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]pyrrolidine-1-carboxylate

6-[1-(Azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (241 mg, 0.78 mmol) is added to a stirred solution of tert-butyl (3S)-3-(trifluoromethanesulfonyloxy) pyrrolidine-1-carboxylate (2.3 mL, 0.78 mmol, 3.4 M in DCM) in DCM (5 mL) at −50° C. under N₂. After the solution is stirred for 1 hr at −50° C., additional tert-butyl (3S)-3-(trifluoromethanesulfonyloxy)pyrrolidine-1-carboxylate (2.3 mL, 0.78. mmol, 3.4 M in DCM) is added and stirring is continued at −50° C. for an additional hr. The mixture is diluted with EtOAc (100 mL) and washed with H₂O (2×20 mL) and brine (20 mL). The combined organic extracts are dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: C18; eluting with a gradient of 35% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a light-yellow solid (80 mg, 20.6%). ES/MS m/z 478.4 [M+H]⁺.

Preparation 401 tert-Butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A stirred RT solution of tert-butyl 4-(4-[5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (500 mg, 1.21 mmol) in DCM (6 mL) is treated with NIS (300 mg, 1.33 mmol) and stirred for 8 hrs at RT. The mixture is diluted with EtOAc (100 mL), washed with H₂O (20 mL), and then brine (20 mL). The combined organic extracts are dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (820 mg, crude), which is used directly without further purification. ES/MS m/z 539.2 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The compound can also be chlorinated with NCS, or with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione. The reaction can be quenched with Na₂SO₃, and the mixture can also be extracted with DCM. Temperature is varied from −60° C. to RT.

TABLE 38 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 402 tert-Butyl 4-(4- [3-iodo-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5- methylpyrazol-1- yl)piperidine-1- carboxylate

629.2 403 tert-Butyl 4-(4-[3-iodo-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- 1,2,3-triazol-1- yl)piperidine-1- carboxylate

630.2 404 tert-Butyl 4-(4-[3-chloro- 5-[(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- 1,2,3-triazol-1- yl)piperidine-1- carboxylate

538.3 405 tert-Butyl 4-[4-[3-chloro- 5-[(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1, 2-a]pyridin-7-yl]-5- methyl-triazol-1- yl]piperidine-1- carboxylate

556.2 406 2-[(1R)-1-([7-Chloro-3- iodoimidazo[1,2- a]pyridin-5- yl]oxy)ethyl]pyridine

400.0 407 tert-Butyl 4-[4-(5-chloro- 3-iodo-imidazo[1,2-a] pyridin-7-yl)-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

542.1 408 tert-Butyl 4-[4-(3-iodo-5- methoxy-imidazo[1,2- a]pyridin-7-yl)-5-methyl- triazol-1-yl]azepane-1- carboxylate

553.0 409¹ tert-Butyl 4-[4-(3-iodo-4- methoxy-pyrazolo[1,5-a] pyridin-6-yl)-5-methyl- triazol-1-yl]piperidine-1- carboxylate

538.7 500 tert-Butyl (2SR,4RS)-2- cyclopropyl-4-[4-(3-iodo- 5-methoxy-imidazo[1,2- a]pyridin-7-yl)-5-methyl- triazol-1-yl]piperidine-1- carboxylate

579.0 ¹Purified by flash silica gel chromatography eluting with 0% to 100% EtOAc in heptane.

Preparation 501 tert-Butyl 4-[4-(3-cyclopropyl-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-(3-iodo-4-methoxy-pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (500 mg, 0.929 mmol) in toluene:H₂O 10:1 (6.6 mL) is added cyclopropylboronic acid (160 mg, 1.86 mmol), K₃PO₄ (986 mg, 4.64 mmol), tricyclohexylphosphane (57.3 mg, 0.204 mmol), and PdOAc₂ (22.9 mg, 0.102 mmol) and the mixture is heated at 100° C. for 16 hr. Upon cooling to RT, the reaction is diluted with EtOAc (20 mL) and H₂O (20 mL), layers are separated, and the aqueous layer is extracted with EtOAc (3×10 mL). The combined organic layers are concentrated in vacuo and the residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in H₂O to afford the title compound (79 mg, 19%). ES/MS m/z 452.9 [M+H]⁺.

Preparation 502 tert-Butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

A solution of tert-butyl 4-(4-[3-iodo-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (800 mg, crude), DMF (8.00 mL), and CuCN (173.01 mg, 1.93 mmol) is stirred for 2 hrs at 100° C. under N₂. The mixture is diluted with DCM (100 mL), washed first with H₂O (20 mL), and next washed with brine (20 mL). The combined organic layers are dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 70% ACN in H₂O (0.1% FA) to give the title compound (450 mg, 46%%). ES/MS m/z 438.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The temperature is varied from 80° C. to 100° C. The reaction can also be quenched with H₂O or NH₄OH aq., and the mixture can be extracted with EtOAc or DCM.

TABLE 39 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 503 tert-Butyl 4-(4-[3-cyano-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

528.4 504 tert-Butyl 4-(4-[3-cyano-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- 1,2,3-triazol-1- yl)piperidine-1-carboxylate

529.3 505 7-Chloro-5-[(1R)-1- (pyridin-2- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

299.1 506 tert-Butyl 4-[4-(5-chloro-3- cyano-imidazo[1,2- a]pyridin-7-yl)-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

441.1 507 tert-Butyl 4-[4-(3-cyano-5- methoxy-imidazo[1,2- a]pyridin-7-yl)-5-methyl- triazol-1-yl]azepane-1- carboxylate

452.0 508¹ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- c]pyrimidin-7-yl]-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

547.2 509 tert-Butyl (2SR,4RS)-4-[4- (3-cyano-5-methoxy- imidazo[1,2-a]pyridin-7-yl)- 5-methyl-triazol-1-yl]-2- cyclopropyl-piperidine-1- carboxylate

478.2 ¹Purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM.

Preparation 510 6-(1-((1r,3r)-3-((tert-Butyldimethylsilyl)oxy)cyclobutyl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-chloro-4-methoxypyrazolo[1,5-a]pyridine

A solution of (1r,3r)-3-(4-(3-Chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (1.03 g, 3.09 mmol), tert-butyldimethylchlorosilane (930 mg, 6.17 mmol) in DCM (15 mL) and imidazole (420 mg, 6.17 mmol) is stirred at RT for 30 min. The reaction is directly loaded onto a silica gel column which is eluting with 0% to 100% EtOAc in heptane to afford the title compound (700 mg, 1.56 mmol) as solid. ES/MS m/z 448.2 [M+H]⁺.

Preparation 511 tert-Butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

NaOH (50% aq.) (8.23 g, 102.856 mmol) is added dropwise to a stirred solution of tert-butyl 4-(4-[3-cyano-5-methoxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (15.00 g, 34.29 mmol) and NDM (10.41 g, 51.43 mmol) in DMA (200.00 mL) at RT under N₂. The mixture is stirred for 2 hrs at 50° C. under N₂. The mixture is diluted with H₂O (1500 mL) and PE (500 mL) and acidified to pH 4 with FA. The precipitated solids are collected by filtration, washed with H₂O (2×50 mL), PE (2×100 mL), and dried under reduced pressure to give the title compound as a white solid (13 g, 89.54%). ES/MS m/z 424.2 [M+H]⁺.

Preparation 512 tert-Butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To tert-butyl 4-[4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (900 mg, 2.18 mmol) and NaOH in water (523.60 mg, 6.55 mmol, 50% in water) in DMA (10 mL) is added dodecane-1-thiol (883 mg, 4.36 mmol) at RT under N₂. The reaction is stirred at 50° C. for 2 hr. Upon cooling to RT, the reaction is diluted with water (150 mL) and PE (50 mL). The pH of the mixture is acidified to pH 4 with FA. The mixture is stirred for 3 hr at RT under N₂. The resultant precipitate is filtered then washed with water (3×10 mL) and PE (3×10 mL). The solids are concentrated under vacuum to afford the title compound as a light-yellow solid (740 mg, 85.12%). ES/MS m/z 399.2 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridine-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 40 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 513¹ tert-Butyl 4-[4-(5- hydroxy-3 imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

413.3 514² tert-Butyl 4-[4-(4- hydroxypyrazolo[1,5- a]pyridin-6-yl)-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

398.0 515 tert-Butyl (3S)-3-[4- (3-cyano-5-hydroxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

424.2 516³ tert-Butyl 4-[4-(3- cyano-5-hydroxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]azepane-1- carboxylate

438.4 517⁴ tert-Butyl (3R)-3-[4- (3-cyano-5-hydroxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

424.2 518 tert-Butyl 4-[4-(3- fluoro-4-hydroxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

417.2 519 Cis-tert-butyl 4-[3-[4-(4- hydroxypyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]cyclobutyl] piperazine- 1-carboxylate

454.2 520⁵ tert-Butyl 4-[4-(3- chloro-4-hydroxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

377.2 [M + 2H − tBu]⁺ 521⁶ tert-Butyl 4-[4-(3- cyclopropyl-4-hydroxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-triazol-1- yl]piperidine-1- carboxylate

438.8 522⁹ tert-Butyl 4-[4-(3- cyano-5-hydroxy- imidazo[1,2- a]pyridin-7-yl)-3-(2- hydroxyethyl)-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

467.1 523⁷ tert-Butyl (2SR,4RS)-4-[4-(3- cyano-5-hydroxy- imidazo[1,2- a]pyridin-7-yl)-5- methyl-triazol-1-yl]- 2-cyclopropyl-piperidine- 1-carboxylate

464.3 524 3-chloro-6-(1- ((1r,3r)-3- hydroxycyclobutyl)- 5-methyl-1H-1,2,3- triazol-4- yl)pyrazolo[1,5-a] pyridin-4-ol

320.0 525 tert-Butyl 2-[4-(3- cyano-4-hydroxy- pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-pyrazol-1-yl]- 7-azaspiro[3.5] nonane-7-carboxylate

407.2^(a) 526 tert-Butyl 2-[4-(3- cyano-5-hydroxy- imidazo[1,2-a]pyridin- 7-yl)-5-methyl-triazol- 1-yl]-7- azaspiro[3.5]nonane- 7-carboxylate

464.2 527 tert-Butyl (3S)-3-[3- [4-(3-cyano-4- hydroxy-pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-pyrazol-1- yl]azetidin-1- yl]pyrrolidine-1- carboxylate

464.2 528⁸ tert-Butyl 4-[4-(3- cyano-5-hydroxy- imidazo[1,2-a]pyridin- 7-yl)-5-methyl-triazol- 1-yl]azepane-1- carboxylate

483.2 ¹Purified by silica gel chromatography eluting with PE: EtOAc (1:2). ²Purified by flash silica gel chromatography eluting with 10% to 70% EtOAc in PE. ³Purified by flash reverse phase chromatography: Column, C18; eluting with 10% to 70% ACN in H₂O (0.1% NH₄CO₃). ⁴Work up: Mixture acidified to pH 6 with FA. Insoluble material collected by filtration. ⁵Purified by silica gel chromatography eluting with 0% to 10% MeOH in DCM. ⁶Purified by flash reverse phase chromatography: Column, C18; eluting with 0% to 100% ACN in H₂O. ⁷Purified by reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H₂O. ⁸Purified by reverse phase chromatography: Column, C18; eluting with 30% to 70% ACN in H₂O (0.1% FA). ^(a)[M + H − C₄H₈]⁺ ⁹Upon adjusting pH to 4 with FA, the resultant insoluble material is collected by filtration.

Preparation 529 tert-Butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

NaOH (50% aq.) (36.57 g, 457.14 mmol) is added dropwise to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (40.00 g, 91.43 mmol) and NDM (55.51 g, 274.28 mmol) in DMA (400 mL) at 0° C. The mixture is stirred for 8 hrs at 50° C. The mixture is diluted with H₂O (400 mL), acidified to pH 6 with FA, filtered, and the filter cake is washed with H₂O, and dried under vacuum. The solid is triturated with a mixture of hexanes (200 mL) and Et₂O (200 mL), filtered, and stirred in MeOH (400 mL) for 2 hrs at 60° C. The mixture is filtered, and the filtered cake is concentrated under vacuum to give the title compound as a light-yellow solid (32 g, 82.6%). ES/MS m/z 424.3 [M+H]⁺.

Preparation 530 tert-Butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate

NaOH (50% aq.) (10.44 g, 130.58 mmol) is added to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (19.00 g, 43.53 mmol) and NDM (26.43 g, 130.58 mmol) in DMA (150 mL) under N₂ and the mixture is stirred for 3 hrs at 60° C. under N₂. The mixture is diluted with H₂O (1 L), acidified to pH˜4 with FA, and extracted with EtOAc (3×1 L). The combined organic extracts are washed with brine (3×800 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is crystallized with MTBE:DCM:MeOH (1000 mL:100 mL:10 mL). The precipitated solids are collected by filtration and washed with hexanes (3×50 mL) to give the title compound as a grey solid (15.03 g, 81.70). ES/MS m/z 421.30 [M−H]⁻.

The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The extraction/washing/drying/crystallization steps can be omitted. The solids can also be washed with H₂O, hexanes, and PE. The solvent can also be 1,4-dioxane. Temperature is varied from 50° C. to 60° C.

TABLE 41 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 531 tert-Butyl (3R)-3-(4- [3-cyano-4- hydroxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)pyrrolidine-1- carboxylate

409.3 532 tert-Butyl (3R)-3-(3- (4-(3-cyano-4- hydroxypyrazolo[1,5- a]pyridin-6-yl)-5- methyl-1H-pyrazol- 1-yl)azetidin-1- yl)pyrrolidine-1- carboxylate

464.3 533 tert-Butyl (3S)-3-(4- [3-cyano-4- hydroxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)pyrrolidine-1- carboxylate

409.2

Preparation 534 tert-Butyl (3S)-3-[3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl] azetidin-1-yl]pyrrolidine-1-carboxylate

To tert-butyl (S)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate (300 mg, 0.64 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (346 mg, 0.97 mmol) in DCM (10.00 mL) is added TEA (196 mg, 1.94 mmol) and DMAP (7 mg, 0.06 mmol) at RT under N₂. The reaction is stirred for 1 hr at RT under N₂ then is concentrated in vacuo. The residue is purified by Prep-TLC 10% MeOH in DCM to afford the title compound as a light-yellow solid (350 mg, 90%). ES/MS m/z 596.2 [M+H]⁺.

Preparation 535 tert-Butyl 4-[4-(3-cyano-4-[[(2S)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5-a]pyridine-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate

A stirred solution of (2R)-1,1,1-trifluoropropan-2-ol (150.00 mg, 1.32 mmol) and DIEA (509.87 mg, 3.95 mmol) in DCM (5.00 mL) is treated with Tf₂O (371.02 mg, 1.32 mmol) at 0° C. under N₂, and the mixture is stirred for 1 hr at RT under N₂. The mixture is added directly to a stirred mixture of tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (100 mg, 0.41 mmol) and K₂CO₃ (168.46 mg, 1.22 mmol) in CAN (8.00 mL). The mixture is stirred for 5 hrs at 80° C. under N₂. The mixture is cooled to RT, the reaction quenched with H₂O (50 mL), and extracted with EtOAc (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC (PE:EtOAc 2:1) to give the title compound as a light-yellow solid (60 mg, 48.89%). ES/MS m/z 504.3 [M-tBu+H]⁺.

The following compound is prepared essentially as described for tert-butyl 4-[4-(3-cyano-4-[[(2S)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5-a]215yridine-6-yl)-5-methylpyrazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 42 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 536 tert-Butyl 4-[4-(3-cyano-4- [[(2R)-1,1,1-trifluoropropan- 2-yl]oxy]pyrazolo[1,5- a]215yridine-6-yl)-5- methylpyrazol-1- yl]piperidine-1-carboxylate

519.1

Preparation 537 tert-Butyl (3S)-3-[3-[4-[3-cyano-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azetidin-1-yl]pyrrolidine-1-carboxylate

To tert-butyl (3S)-3-[3-[4-[3-cyano-4-(trifluoromethylsulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]azetidin-1-yl]pyrrolidine-1-carboxylate (350 mg, 0.58 mmol) and (1R)-1-(pyridin-2-yl)ethanamine (358 mg, 2.93 mmol) in toluene (10 mL) at RT is added Cs₂CO₃ (765 mg, 2.35 mmol), XantPhos (68 mg, 0.11 mmol) and Pd₂(dba)₃ (53 mg, 0.05 mmol). The reaction is stirred overnight at 100° C. under N₂. Upon cooling to RT, the reaction is concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with DCM;MeOH (20:1 to 10:1) to afford the title compound as a green solid (60 mg, 17%). ES/MS m/z 568.4 [M+H]⁺.

Preparation 538 tert-Butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-methyl-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To tert-Butyl 4-(4-{5-hydroxy-3-methylimidazo[1,2-a]pyridin-7-yl}-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (600.0 mg, 1.46 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethyl methanesulfonate (382.66 mg, 1.75 mmol) in DMF (10.0 mL) is added Cs₂CO₃ (1.42 g, 4.37 mmol) RT under N₂. The reaction is stirred at 120° C. for 2 hr. Upon cooling to RT, the mixture is diluted with H₂O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (3×100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by Prep-TLC (DCM/MeOH 20:1) to afford the title compound as a yellow solid (240 mg, 30.8%). ES/MS m/z 536.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-methyl-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times and temperature, and adjusting the purification system as appropriate.

TABLE 43 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 539^(1,2) tert-Butyl 4-[4-[3-cyano-4- [1-(2- methoxycarbonylphenyl) ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

586.3 540³ tert-Butyl 4-[4-[3-cyano-4- [1-[2-(dimethylcarbamoyl) phenyl]ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine- 1-carboxylate

599.3 541³ tert-Butyl 4-[4-[3-cyano-4- [2-(5-fluoro-2-pyridyl)-2- oxo-ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- . triazol-1-yl]piperidine-1- carboxylate

554.4 542³ tert-Butyl 4-[4-[3-chloro-4- [2-(5-fluoro-2-pyridyl)-2- oxo-ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

514.2 [M + H − tBu]⁺ 543⁴ tert-Butyl 4-[4-[3-cyano- 5-[(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-3-(2- hydroxyethyl)-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

590.1 544⁵ tert-Butyl 4-[4-[3-cyano- 5-[(1R)-1-[4-(2,2,2- trifluoroethyl)-1,2,4-triazol- 3-yl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine- 1-carboxylate

601.5 545⁶ (1s,3r)-3-(4-(4-((S)-2- ((tert-Butyldimethylsilyl) oxy)-1-(5-fluoropyridin-2- yl)ethoxy)-3- chloropyrazolo[1,5- a]pyridin-6-yl)-5-methyl- 1H-1,2,3-triazol-1- yl)cyclobutan-1-ol

573.0 ¹Methyl 2-(1-bromoethyl)benzoate used as starting material. ²Purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in H₂O. ³Purified by reverse phase chromatography eluting with a gradient of 10% to 100% ACN in H₂O. ⁴Purified by Prep-TLC 2:1 EtOAc:PE. ⁵Purified by Prep-TLC 10:1 DCM:MeOH. ⁶Purified by silica gel chromatography eluting with a gradient of 0% to 20% MeOH in DCM.

Preparation 546 tert-Butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (45 mg, 0.08 mmol) in MeOH (5 mL) is added NaBH₄ (3.7 mg, 0.098 mmol). The reaction is stirred for 30 min. at RT then concentrated under reduced pressure. The residue is treated with EtOAc and H₂O. The organic layer is separated, and the aqueous layer is extracted with EtOAc (2×10 mL). The combined organic layers are washed brine, dried over Na₂SO₄, and concentrated to afford the title compound (45 mg, 0.08 mmol) as a white solid. The crude product is used in the next without further purification. ES/MS m/z 556.2 [M+H]⁺.

The following compound is prepared essentially as described for tert-Butyl 4-[4-[3-cyano-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction time and temperature, and adjusting the purification system as appropriate.

TABLE 44 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺]⁺ 547 tert-Butyl 4-[4-[3-chloro-4- [2-(5-fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

572.2

Preparation 548 tert-Butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-[3-chloro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (200 mg, 0.35 mmol) in THF (10 mL) at RT is added a solution of MeMgBr (3M in Et2O) (50.2 mg, 0.42 mmol). After stirring at RT for 60 min. the reaction is quenched with sat. NH₄Cl, extracted with EtOAc (2×), dried over Na₂SO₄ and concentrated. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford the title compound (170 mg, 82.7%) as a white solid. ES/MS, m/z 586.4 [M+H]⁺.

Preparation 549 tert-Butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-hydroxy-propoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-[4-[3-fluoro-4-[2-(5-fluoro-2-pyridyl)-2-oxo-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (180 mg, 0.33 mmol) in THF (8 mL) at RT is added MeMgBr (3M solution) (58.2 mg, 0.49 mmol) and the reaction is stirred at RT for 30 min. Next, the reaction is quenched with sat. NH₄Cl, extracted into EtOAc (2×), dried over Na₂SO₄ and concentrated. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in heptane to afford the title compound (90 mg, 49%) as a white solid. ES/MS, m/z 570.4 [M+H]f.

Preparation 550 tert-Butyl4-(4-{4-[2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethoxy]-3-cyanopyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylate

To a stirred mixture of PPh₃ (9.93 g, 97.87 mmol) in THF (30 mL) is added DIAD (7.66 g, 37.87 mmol) dropwise at 0° C. under N₂. The reaction is stirred at 0° C. for 0.5 hr under N₂. To the mixture is added 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (1.93 g, 7.10 mmol) and tert-butyl 4-(4-{3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl}-5-methylpyrazol-1-yl)piperidine-1-carboxylate (2 g, 4.73 mmol) in THF (20 mL). The resulting mixture is stirred for 2 hr at RT then concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 80% to 100% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (2.7 g, 85.9%). ES/MS, m/z 676.4 [M+H]⁺.

Preparation 551 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To PPh₃ (789.88 mg, 3.01 mmol) in THF (15 mL) is added DIAD (568.36 mg, 2.811 mmol) dropwise at 0° C. under N₂. The reaction is stirred at 0° C. for 0.5 hr. To the mixture is added to tert-butyl 4-[4-(4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-triazol-1-yl]piperidine-1-carboxylate (400 mg, 1.00 mmol) and 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethanol (408.68 mg, 1.51 mmol) in THF (10 mL). After stirring 2 hr at RT, the reaction is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 70% to 80% ACN in H2O (0.1% NH₄HCO₃) to give the title compound as a light-brown oil (450 mg, 68.77%). ES/MS, m/z 652.4 [M+H]⁺.

Preparation 552 tert-Butyl 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate

DEAD (185.1 mg, 1.06 mmol) is added to a stirred solution of PPh₃ (278.7 mg, 1.06 mmol) in THF (5.0 mL) at 0° C. under N₂ After the mixture is stirred for 30 min at 0° C. under N₂, a solution of tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (150.0 mg, 0.35 mmol) and (1S)-1-(5-fluoropyridin-2-yl)ethanol (60.0 mg, 0.425 mmol) in THF (5.0 mL) is added to the mixture at RT under N₂ and stirred overnight at RT. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 70% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a yellow solid (80.0 mg, 41.3%). ES/MS m/z 547.2 [M+H]⁺.

Preparation 553 tert-Butyl 4-[4-[3-cyano-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

DIAD (334.25 mg, 1.65 mmol) is added dropwise to a stirred mixture of PPh₃ (464.52 mg, 1.77 mmol) in THF (10 mL) at 0° C. under N₂ and the mixture is stirred for 30 min. at 0° C. under N₂. To the mixture is added to 1-[5-(trifluoromethyl)pyridin-3-yl]ethanol (135.42 mg, 0.71 mmol) and tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (250.00 mg, 0.59 mmol) in THF (20 mL). The mixture is stirred overnight at RT and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18; eluting with 0 to 100% ACN in H₂O (0.1% FA) give the title compound (150 mg, 42.59%) as an off-white solid. ES+H, m/z 596.9 [M+H]⁺

Preparation 554 tert-Butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

DIAD (171.90 mg, 0.85 mmol) is added dropwise to a stirred mixture of PPh₃ (241.55 mg, 0.92 mmol) in THF (10.00 mL) at 0° C. under N₂. The mixture is stirred for 30 min. at 0° C. under N₂, then the mixture is added to 1-(5-fluoropyridin-2-yl)-2-methoxyethanol (133.39 mg, 0.78 mmol) and tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture is stirred for 2 hr at RT under N₂ and concentrated under vacuum. The residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (160 mg, 39.17%) as an off-white solid. ES/MS, m/z 577.3 [M+H]⁺.

Preparation 555 tert-Butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

DIAD (171.90 mg, 0.85 mmol) is added dropwise to a stirred mixture of PPh₃ (241.55 mg, 0.92 mmol) in THF (10.0 mL) at 0° C. under N₂ and the mixture is stirred for 30 min at 0° C. under N₂. The mixture is added to 1-(5-fluoropyridin-2-yl)propan-1-ol (120.92 mg, 0.78 mmol) and tert-butyl-4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (300.00 mg, 0.71 mmol) in THF (10 mL). The mixture is stirred for 2 hr at RT under N₂. The mixture is concentrated under reduced pressure and the residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (210 mg, 52.87%) as a grey solid. ES/MS m/z 561.5 [M+H]⁺.

Preparation 556 tert-Butyl 4-[4-[3-cyano-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

DIAD (143.25 mg, 0.71 mmol) is added dropwise to a stirred mixture of PPh₃ (201.29 mg, 0.77 mmol) in THF (15.00 mL) at 0° C. under N₂ and the mixture is stirred for 30 min at 0° C. under N₂. To the mixture is added to 1-(5-fluoropyridin-2-yl)-2-methoxyethanol (111.16 mg, 0.65 mmol) and tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (250.00 mg, 0.59 mmol) in THF (15 mL). The mixture is stirred for 2 hr at RT under N₂ and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (200 mg, 58.75%) as an off-white solid. ES/MS m/z 577.1⁺.

The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. DIAD, DIEA and DMAP can also be used in lieu of DEAD. Temperature is varied from 0° C. to 80° C. Polymer supported PPh₃ can be used in place of PPh₃.

TABLE 45 ES/MS Prep m/z No. Chemical Name Structure [[M + H]⁺ 557¹ tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(oxan-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

535.3 558¹ tert-Butyl 4-(4-[3-cyano-4- [(3-fluoropyridin-2- yl)methoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

532.3 559 tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(3-fluoropyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

546.2 560¹ tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(pyrazin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

529.3 561¹ tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(2-methylpyrazol-3- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

531.3 562 tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(pyridin-2- yl)propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

542.3 563 tert-Butyl 4-(4-[3-cyano-4- [(1R)-1-(1-methylpyrazol-3- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1-carboxylate

531.4 564 tert-Butyl 4-(4-(3-cyano-4- (((7R)-6,7-dihydro-5H- cyclopenta[b]pyridin-7- yl)oxy)pyrazolo[1,5- a]pyridin-6-yl)-5-methyl- 1H-1,2,3-triazol-1- yl)piperidine-1-carboxylate

541.3 565² tert-Butyl 4-(4-[3-cyano-4- [(1R)-1- cyclohexylethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-1,2,3-triazol-1- yl)piperidine-1-carboxylate

534.5 566¹ tert-Butyl 4-[4-(3-cyano-4- [[2-(pyridin-2-yl)propan-2- yl]oxy]pyrazolo[1,5- a]pyridin-6-yl)-5- methylpyrazol-1- yl]piperidine-1-carboxylate

542.4 567 tert-Butyl 4-[4-[3-cyano-4- [2-methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

627.2 568 tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

546.4 569 tert-Butyl 4-[4-[5-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)ethoxy]- 3-cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

677.5 570⁵ tert-Butyl 4-[4-[4-[3-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2- pyridyl)propoxy]-3-cyano- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

691.4 571 tert-Butyl 4-[4-[4-[(1R)-1- (5-fluoro-2-pyridyl) ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

522.4 572⁶ tert-Butyl 4-[4-[3-cyano-4- [1-(5-methylpyridazin-3- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

544.3 573¹ tert-Butyl 4-[4-[3-cyano-5- [[(7R)-6,7-dihydro-5H- cyclopenta[b]pyridin-7- yl]oxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

541.3 574⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(4- isoquinolyl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

579.3 575⁶ tert-Butyl 4-[4-[3-cyano-4- [1-(7-fluoro-4- isoquinolyl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

596.3 576⁷ tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- (4-isoquinolyl)ethoxy]-3- cyano-pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

709.3 577⁵ tert-Butyl 4-[4-[3-cyano-4- [1-(5-methylthiazol-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

549.3 578⁸ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(2-pyridyl) propoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate, Isomer 2

543.3 579⁹ tert-Butyl 4-[4-[3-cyano-4- [2-fluoro-1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

508.7 [M + H − C₄H₉]⁺ 580⁷ tert-butyl 4-[4-[3-cyano-4- [cyclopropyl-(5-fluoro-2- pyridyl)methoxy]pyrazolo [1,5-a]pyridin- 6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

572.8 581⁷ tert-Butyl 4-[4-[3-cyano-4- [(1-fluorocyclopropyl)-(5- fluoro-2- pyridyl)methoxy]pyrazolo [1,5-a]pyridin- 6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

590.8 582¹⁰ tert-Butyl 4-[4-[3-cyano-4- [(5-fluoro-2-pyridyl)-[1- (trifluoromethyl) cyclopropyl] methoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

641.3 583¹⁵ tert-Butyl 2-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)ethoxy]- 3-cyano-pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- pyrazol-1-yl]-7- azaspiro[3.5]nonane- 7-carboxylate

716.5 584⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(2-methyltriazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

533.2 585⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(1-isopropyltriazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

533.2 586⁴ tert-Butyl 4-[4-[5-[2-[tert- butyl(dimethyl)silyl]oxy-1- [5-(trifluoromethyl)-3- pyridyl]ethoxy]-3-cyano- imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

727.4 587⁴ tert-Butyl 4-[4-[5-[2-[tert- butyl(dimethyl)silyl]oxy-1- (3,5-difluoro-2- pyridyl)ethoxy]-3-cyano- imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

695.4 588¹¹ tert-Butyl 2-[4-[5-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)ethoxy]- 3-cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]-7- azaspiro[3.5]nonane-7- carboxylate

717.4 589¹² tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)ethoxy]- 3-cyano-pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

677.4 590¹³ tert-Butyl 4-[4-[5-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-chloro-2-pyridyl)ethoxy]- 3-cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

693.6 591⁵ tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- [5-(trifluoromethyl)-3- pyridyl]ethoxy]-3-cyano- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

727.4 592¹⁴ tert-Butyl 4-[4-[5-[3-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2- pyridyl)propoxy]-3-cyano- imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

691.5 593⁸ tert-Butyl 4-[4-[3-cyano-5- [2-methoxy-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate, Isomer 1

559.3 594⁸ tert-Butyl 4-[4-[3-cyano-5- [3-methyl-1-(2- pyridyl)butoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

571.4 595¹⁶ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(3- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

529.2 596⁸ tert-Butyl 4-[4-[3-cyano-5- [2-cyclopropyl-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

569.3 597¹⁷ tert-Butyl 4-[4-[3-cyano-5- (3,4-dihydro-2H-pyrano [3,2-b]pyridin-4- yloxy)imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

557.25 598⁸ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(3-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.1 599⁸ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(2- fluorophenyl)ethoxy] imidazo[1,2-a]pyridin- 7-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

546.2 600¹⁸ tert-Butyl 4-[4-[3-cyano-5- [(6,6-dimethyl-5,7- dihydrocyclopenta [b]pyridin-7-yl) oxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine- 1-carboxylate

569.3 601¹⁹ tert-Butyl 4-[4-[3-cyano-5- [1-(3,5-difluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

565.1 602⁸ tert-Butyl 4-[4-[3-cyano-5- [2-pyridyl-[1- (trifluoromethyl) cyclopropyl]methoxy] imidazo[1,2- a]pyridin-7-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

623.0 603²⁰ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methyl-2-pyridyl) ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

543.3 604²¹ tert-Butyl 4-[4-[3-cyano-5- (1-isothiazol-4-ylethoxy) imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

535.1 605²² tert-Butyl 4-[4-[3-cyano-5- (1-isothiazol-3- ylethoxy)imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

535.10 606²⁰ tert-Butyl 4-[4-[3-cyano-4- [1-[5-(trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

597.3 607²³ tert-Butyl 4-[4-[3-cyano-5- (1-isothiazol-5- ylethoxy)imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

535.2 608²⁴ tert-Butyl 4-[4-[4-[(1R)-1- (2-bromophenyl) ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-pyrazol-1- yl]piperidine-1-carboxylate

582.2 609 tert-Butyl 4-[4-[3-cyano-4- [1-(2- methylsulfonylphenyl) ethoxy]pyrazolo [1,5-a]pyridin-6- yl]-5-methyl-pyrazol-1- yl]piperidine-1-carboxylate

627.2 [M + Na]⁺ 610⁹ tert-Butyl 4-[4-[5-[1-(1,3- benzothiazol-7-yl)ethoxy]-3- cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

585.2 611²⁵ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(2-pyridyl)ethoxy] imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]azepane-1-carboxylate

543.3 612⁸ tert-Butyl (3S)-3-[4-[3- cyano-5-[(1R)-1- (5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.2 613²⁶ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]azepane-1- carboxylate

561.5 614²⁷ tert-Butyl (3R)-3-[4-[3- cyano-5-[(1R)-1- (5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.2 615⁶ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-pyrimidin-4- ylethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

530.2 616⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(2-ethyltriazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine- 1-carboxylate

547.3 617²⁹ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methoxy-3- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine- 1-carboxylate

559.4 618³⁰ tert-Butyl 4-[4-[5-[1-(6- chloro-3-pyridyl)ethoxy]-3- cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

(³⁵Cl/³⁷Cl) 563.3/ 565.3 619³¹ tert-Butyl 4-[4-[3-cyano-5- [1-[5- (trifluoromethyl)isoxazol-3- yl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

587.2 620³² tert-Butyl 4-[4-[3-cyano-5- [2,2-dimethyl-1-(2- pyridyl)propoxy]imidazo [1,2-a]pyridin-7- yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate, Isomer 1

571.2 621⁸ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(2,6- difluorophenyl)ethoxy] imidazo[1,2-a] pyridin-7-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

564.3 622⁷ tert-Butyl 4-[4-[3-cyano-4- [1-[5-(difluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridin-6- yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

579.2 623⁹ tert-Butyl 4-[4-[3-cyano-4- [1-(5-methyl-3- pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

543.3 624⁹ tert-Butyl 4-[4-[3-cyano-4- [1-(5-methyl-1,3,4- thiadiazol-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

548.3 [M − H]⁺ 625⁹ tert-Butyl 4-[4-[3-cyano-4- [1-[2-morpholino-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

a 626⁹ tert-Butyl 4-[4-[3-cyano-5- [1-(1-isopropyltriazol-4- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

561.3 627⁹ tert-Butyl 4-[4-[3-cyano-5- [1-(6-methylpyrazin-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

544.3 628⁶ tert-Butyl 4-[4-[3-cyano-5- [1-(3,3- difluorocyclobutyl)ethoxy] imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

542.2 629⁶ tert-Butyl 4-[4-[5-[(1R)-1- (2-chloro-4-fluoro- phenyl)ethoxy]-3-cyano- imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

580.2 630³³ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(5-fluoro- 3-methyl-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

561.3 631³⁴ tert-Butyl 4-[4-[3-cyano-5- [2,2-difluoro-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

583.2 632⁷ tert-Butyl 4-[4-[3-cyano-4- [(1R)-1-(2-methylthiazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

549.2 663⁷ tert-Butyl 4-[4-[3-cyano-4- [(1R)-1-(1-methylpyrazol-3- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

532.2 634³⁵ tert-Butyl 4-[4-[3-cyano-5- [(5-fluoro-2- pyridyl)methoxy]imidazo [1,2-a]pyridin-7- yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

533.2 635³⁵ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(2,4- difluorophenyl)ethoxy] imidazo[1,2-a] pyridin-7-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

564.2 636²⁶ tert-Butyl 4-[4-[3-cyano-5- [(5-fluoro-2-pyridyl)-[1- (trifluoromethyl)cyclopropyl] methoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

641.5 637⁶ tert-Butyl 4-[4-[4-[1-(1,2- benzothiazol-7-yl)ethoxy]-3- cyano-pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

585.2 638⁷ tert-Butyl 4-[4-[5-[1-(1,2- benzothiazol-7-yl)ethoxy]-3- cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

585.2 639⁵ tert-Butyl 4-[4-[3-cyano-5- [(1R)-1-(4-fluorophenyl) ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

546.1 640³¹ tert-Butyl 4-[4-[3-cyano-5- [2-methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

627.2 641⁴ tert-Butyl 4-[4-[3-cyano-5- [1-(2-isoxazol-3-ylphenyl) ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

595.3 642³⁶ tert-Butyl 4-[4-[3-cyano-4- [1-(3- methylsulfonylphenyl) ethoxy]pyrazolo [1,5-a]pyridin-6- yl]-5-methyl-pyrazol-1- yl]piperidine-1-carboxylate

505.20 [M + H − C₅H₉O₂]⁺ 643²⁶ tert-Butyl 4-[4-[3-cyano-5- [1-(5-fluoro-3- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.4 644³⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(5-fluoro-2-pyridyl)-2- methoxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

577.1 645³⁸ tert-Butyl 4-[4-[5-[(1R)-1- (5-chloro-2-pyridyl)ethoxy]- 3-cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

563.3 646²⁹ tert-Butyl 4-[4-[5-[1-(5- chloro-3-pyridyl)ethoxy]-3- cyano-imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

563.4 647³⁵ tert-Butyl 4-[4-[3- cyano-5-[1-(3- methylsulfonylphenyl) ethoxy]imidazo [1,2-a]pyridin-7- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

606.2 648³⁵ tert-Butyl 4-[4-[3-cyano-5- [1-(2-isothiazol-3- ylphenyl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

611.2 649⁹ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methyl-1,3,4- thiadiazol-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

550.2 650⁷ tert-butyl 4-[4-[3-cyano-4- [1-(4-methylisothiazol-5- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.3 [M − H]⁺ 651³³ tert-Butyl 4-[4-[3-cyano-4- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.2 652¹⁷ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methylthiazol-2- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

549.3 653³⁹ tert-Butyl 4-[4-[3-cyano-4- [2-methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

627.2 654⁴⁰ tert-Butyl 4-[4-[5-[1-(5- chloropyridazin-3- yl)ethoxy]-3-cyano- imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

564.2 655⁶ tert-Butyl 4-[4-[4-[1-(5- chloropyridazin-3- yl)ethoxy]-3-cyano- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

[Cl³⁵/Cl³⁷] 564.2/ 566.2 656⁴¹ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methyl-3- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

543.3 657⁴¹ tert-Butyl 4-[4-[3-cyano-5- [1-[5-(difluoromethyl)-3- pyridyl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

579.2 658⁷ tert-Butyl 4-[4-[3-cyano-4- [1-(1-methylpyrrolo[2,3- c]pyridin-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

582.3 659⁹ tert-Butyl 4-[4-[3-cyano-4- [1-(6-methylpyrazin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

544.3 660⁶ tert-Butyl 4-[4-[3-cyano-5- [1-(5-methylpyridazin-3- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

544.3 661⁴² tert-Butyl 4-[4-[3-cyano-5- [1-(3-ethyltriazol-4- yl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

547.2 662⁴³ tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- (5-fluoro-2-pyridyl)ethoxy]- 3-fluoro-pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

670.3 663^(44,45) tert-Butyl 4-[4-[4-[2-[tert- butyl(dimethyl)silyl]oxy-1- (2-pyridyl) ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

634.4 664⁴⁶ Cis-tert-Butyl 4-[3-[4-[4-[2- [tert-butyl(dimethyl) silyl]oxy-1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]cyclobutyl] piperazine-1-carboxylate

707.1 665⁷ tert-Butyl 4-[4-[3- cyclopropyl-4-[(1R)-1-(5- fluoro-2-pyridyl)ethoxy] pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

561.8 666⁹ tert-Butyl 4-[4-[4-[2-cyano- 1-(5-fluoro-2-pyridyl)-2- methyl-propoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1-carboxylate

575.7 667⁹ tert-Butyl 4-[4-[3-cyano-4- [1-[2-(2- methoxyethylamino)-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

670.3 668 tert-Butyl 4-[4-[4-[1-[2-[3- [tert-butyl(dimethyl) silyl]oxyazetidin-1-yl]-5- (trifluoromethyl)-3- pyridyl]ethoxy]-3-cyano- pyrazolo[1,5-a]pyridin-6- yl]-5-methyl-triazol-1- yl]piperidine-1-carboxylate

b 669⁴⁷ tert-Butyl 4-[4-[3-cyano-5- [1-(5-fluoro-2-pyridyl)-2- (trifluoromethoxy)ethoxy] imidazo[1,2-a]pyridin-7-yl]- 5-methyl-triazol-1- yl]piperidine-1-carboxylate

631.1 670⁵ tert-Butyl 4-[4-[3-cyano-5- [1-[5-fluoro-6-(2- methoxyethoxy)-2- pyridyl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

621.5 671⁹ tert-Butyl 4-[4-[3-cyano-5- [1-[5-(trifluoromethoxy)-3- pyridyl]ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

613.1 672²⁶ tert-Butyl (2SR,4RS)-4-[4- [3-cyano-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]-2-cyclopropyl- piperidine-1-carboxylate

569.2 673⁹ tert-Butyl 4-[4-[4-[[(4R)- 2,2-dimethyl-1,3-dioxolan- 4-yl]-(5-fluoro-2- pyridyl)methoxy]pyrazolo [1,5-a]pyridin- 6-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

608.8 674⁴⁸ tert-Butyl 4-[4-[5-[(1R)-1- (5-fluoro-2- pyridyl)ethoxy]imidazo[1,2- c]pyrimidin-7-yl]-5-methyl- pyrazol-1-yl]piperidine-1- carboxylate

522.2 ¹Purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (2:1 to 1:1) ²Flash chromatography eluting with 71% PE in EtOAc. ³Purified by reversed Combi-flash chromatography, C18 column, eluting with 80% to 100% ACN in H₂O (0.1% NH₄HCO₃). ⁴Purified by reverse phase chromatography, C18 column, eluting with 70% to 80% ACN in H₂O (0.1% NH₄HCO₃). ⁵Purified by reverse phase chromatography, C18 column, eluting with 50% to 60% ACN in H₂O (0.1% NH₄HCO₃). ⁶Purified by reverse phase chromatography, C18 column, eluting ACN in H₂O. ⁷Purified by reverse phase chromatography, C18 column, eluting with 0% to 100% ACN in H₂O. ⁸Purified by prep-TLC, eluting with a gradient of PE:EtOAc (1:1). ⁹Purified by reverse phase chromatography, C18 column, eluting with 10% to 100% ACN in H₂O. ¹⁰Purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (8:1). ¹¹Purified by reverse phase chromatography, C18 column, eluting with 45% to 50% ACN in H₂O (0.1% FA). ¹²Purified by reverse phase chromatography, C18 column, eluting with 56% to 60% ACN in H₂O (0.1% NH₄HCO₃). ¹³Purified by reverse phase chromatography, C18 column, eluting with 70% to 75% ACN in H2O (0.1% NH₄OH). ¹⁴Purified by reverse phase chromatography, C18 column, eluting with 70% to 90% ACN in H2O (0.1% NH₄HCO₃). ¹⁵Purified by reverse phase chromatography, C18 column, eluting with 80% to 100% ACN in H2O (0.1% NH₄HCO₃). ¹⁶Purified by prep-TLC, eluting with EtOAc. ¹⁷Purified by silica gel column chromatography, eluting with PE:EtOAc (5:1 to 2:1). ¹⁸Purified by prep-TLC, eluting with a gradient of PE:EtOAc (2:1). ¹⁹Purified by reverse phase chromatography, C18 column, eluting with 0% to 100% ACN in H₂O (0.1% FA). ²⁰Purified by reverse phase chromatography, C18 column, eluting with 60% to 70% ACN in H₂O (0.1% NH₄HCO₃). ²¹Purified by reverse phase chromatography, C18 column, eluting with 30% to 50% ACN in H2O (0.1% NH₄OH). ²²Purified by reverse phase chromatography, C18 column, eluting with 20% to 60% ACN in H₂O (NH₄HCO₃). ²³Purified by silica gel column chromatography, eluting with a gradient of DCM:MeOH (9:1). ²⁴Purified by silica gel column chromatography, eluting with 10% to 50% EtOAc in PE. ²⁵Purified by reverse phase chromatography, C18 column, eluting with 10% to 50% ACN in H₂O (0.1% FA). ²⁶Purified by reverse phase chromatography, C18 column, eluting with 10% to 50% ACN in H2O (0.1% NH₄HCO₃). ²⁷Purified by reverse phase chromatography, C18 column, eluting with 30% to 45% ACN in H₂O (0.1% NH₃ H₂O). ²⁸Purified by reverse phase chromatography, C18 column, eluting with 0% to 100% ACN in H₂O (0.1% NH₄HCO₃). ²⁹Purified by reverse phase chromatography, C18 column, eluting with 10% to 70% ACN in H₂O (0.1% NH₄HCO₃). ³⁰Purified by reverse phase chromatography, C18 column, eluting with 40% to 80% ACN in H₂O (0.05% NH₄HCO₃). ³¹Purified by reverse phase chromatography, C18 column, eluting with 45% to 50% ACN in H₂O (0.1% NH₄HCO₃). ³²Purified by reverse phase chromatography, C18 column, eluting with 50% to 70% ACN in H₂O (0.1% FA). ³³Purified by reverse phase chromatography, C18 column, eluting with 30% to 50% ACN in H2O (0.1% NH₄HCO₃). ³⁴Purified by reverse phase chromatography, C18 column, eluting with 25% to 50% ACN in H2O (0.1% NH₄OH). ³⁵Purified by reverse phase chromatography, C18 column, eluting ACN in H₂O (0.1% FA). ³⁶Purified by silica gel chromatography, eluting with EtOAc:Hepane. ³⁷Purified by reversed Combi-flash chromatography, C18 column, eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃). ³⁸Purified by reverse phase chromatography, C18 column, eluting with 40% to 50% ACN in H₂O. ³⁹Purified by reverse phase chromatography, C18 column, eluting with 10% to 50% ACN in H₂O. ⁴⁰Purified by reverse phase chromatography, C18 column, eluting with 0% to 50% ACN in H₂O. ⁴¹Purified by reverse phase chromatography, C18 column, eluting with 10% to 100% ACN in H₂O. ⁴²Purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (4:1 to 3:1). ⁴³Purified by reverse phase chromatography, C18 column, eluting with 85% to 95% ACN in H₂O (0.1% FA). ⁴⁴Purified by silica gel column chromatography, eluting with a gradient of PE:EtOAc (1:1). ⁴⁵Purified by reverse phase chromatography, C18 column, eluting with 60% to 90% ACN in H2O. ⁴⁶Purified by reverse phase chromatography, C18 column, eluting with 85% to 95% ACN in H2O (0.1% NH₄HCO₃). ⁴⁷Purified by reverse phase chromatography, C18 column, eluting with 50% to 55% ACN in H2O (0.1% NH₄HCO₃). ⁴⁸Purified by silica gel column chromatography, eluting with a gradient of 0% to 100% acetone in DCM. a¹H NMR (400 MHz, CDCl₃) δ 1.49-1.54 (m, 9 H), 1.91-1.97 (m, 3 H), 2.00 (s, 3 H), 2.20-2.33 (m, 2 H), 2.43-2.49 (m, 3 H), 2.89-3.01 (m, 2 H), 3.25-3.34 (m, 4 H), 3.93-4.01 (m, 3 H), 4.25-4.37 (m, 3 H), 5.78-5.88 (m, 1 H), 7.35-7.42 (m, 1 H,) 8.13-8.18 (m, 2H), 8.18-8.24 (m, 1 H), 8.48-8.54 (m, 1 H). b¹H NMR (400 MHz, CDCl₃) δ 0.00 (br s, 6 H) 0.81 (br s, 9H) 1.39 (br s, 9H) 1.71-1.83 (m, 3 H) 1.92 (br d, J = 15.53 Hz, 3 H) 2.08-2.21 (m, 2 H) 2.26 (br s, 3 H) 2.77-2.95 (m, 2 H) 3.91-4.12 (m, 2 H) 4.15-4.33 (m, 4 H) 4.39-4.52 (m, 1 H) 4.68-4.79 (m, 1 H) 5.43-5.54 (m, 1 H) 6.85-6.99 (m, 1 H) 7.79-7.94 (m, 1 H) 8.05-8.17 (m, 1 H) 8.22-8.37 (m, 2 H).

Preparation 675 tert-Butyl (3R)-3-(3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate

A stirred mixture of tert-butyl (R)-3-(3-(4-(3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate (300 mg, 0.64 mmol) and 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (346 mg, 0.97 mmol) in DCM (10.00 mL) is treated with TEA (196.00 mg, 1.94 mmol) and DMAP (7.00 mg, 0.06 mmol) and stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure. The residue is purified by Prep-TLC, eluting with a gradient of DCM:MeOH (10:1) to give the title compound as a light-yellow oil (350 mg, 90.8%). ES/MS m/z 596.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl (R)-3-(3-(4-(3-cyano-4-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-pyrazol-1-yl)azetidin-1-yl)pyrrolidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. DMF can also be used as the solvent and DIEA can be used as the base. Temperature is varied from 0° C. to RT.

TABLE 46 ES/MS Prep m/z No. Chemical Name Structure [[M + H]⁺ 676¹ tert-Butyl (3S)-3-(4-(3-cyano-4- (((trifluoromethyl)sulfonyl)oxy) pyrazolo[1,5-a]pyridin-6-yl)-5- methylpyrazol-1-yl)pyrrolidine- 1-carboxylate

541.3 677² tert-Butyl (3R)-3-[4-[3-cyano-4- (trifluoromethanesulfonyloxy) pyrazolo[1,5-a]pyridin-6-yl]-5- methylpyrazol-1-yl]pyrrolidine- 1-carboxylate

541.0 678³ tert-Butyl 4-[4-[3-cyano-4- (trifluoromethylsulfonyloxy) pyrazolo[1,5-a]pyridin-6-yl]-5- methyl-pyrazol-1-yl]piperidine- 1-carboxylate

506.4 ¹Purification with reverse Combi-flash chromatography with C18 column; eluting with 70-75% ACN in H₂O. ²Purification with reverse flash chromatography with C18 column eluting with 60-70% ACN in H2O (1% NH₄HCO₃). ³Purified by silica gel column chromatography, eluting with PE:EtOAc (10:1)

Preparation 679 tert-Butyl (3R)-3-[4-(3-cyano-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate

A stirred mixture of tert-butyl (3R)-3-[4-[3-cyano-4-(trifluoromethanesulfonyloxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate (102.00 mg, 0.19 mmol) and (1R)-1-(pyridin-2-yl)ethanamine (27.67 mg, 0.23 mmol) in toluene (20.00 mL) is treated with Cs₂CO₃ (184.45 mg, 0.57 mmol), Xantphos (65.51 mg, 0.11 mmol) and Pd₂(dba)₃ (86.40 mg, 0.094 mmol) added in portions at RT under N₂. The mixture is stirred for 4 hrs at 80° C. under N₂. The solution is cooled to RT, filtered, the filter cake washed with EtOAc (5×50 mL), and the filtrate concentrated under reduced pressure. The residue is purified by reverse flash chromatography with the following conditions: C18 silica gel; H₂O (0.1% NH₄HCO₃) in ACN, eluting with a gradient of 70% to 80%. The mixture is concentrated under reduced pressure to give the title compound as a white solid (50 mg, 51.69%). ES/MS m/z 513.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl (3R)-3-[4-(3-cyano-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]pyrrolidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The catalyst can also be Pd(OAc)₂, Pd(dba)₂. Temperature is varied from 80° C. to 100° C.

TABLE 47 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 680¹ tert-Butyl (R)-3-(3-(4-(3- cyano-4-(((R)-1- (pyridin-2- yl)ethyl)amino)pyrazolo [1,5-a]pyridin-6-yl)-5- methyl-1H-pyrazol-1- yl)azetidin-1- yl)pyrrolidine- 1-carboxylate

568.4 681² tert-Butyl (3S)-3-[4-(3- cyano-4-[[(1R)-1- (pyridin-2- yl)ethyl]amino]pyrazolo [1,5-a]pyridin-6-yl)-5- methylpyrazol-1- yl]pyrrolidine-1- carboxylate

513.1 682³ tert-Butyl 4-[4-[3-cyano- 4-[[(1R)-1-(2-pyridyl) ethyl]amino] pyrazolo[1,5-a]pyridin- 6-yl]-5-methyl-pyrazol- 1-yl]piperidine-1- carboxylate

527.4 683⁴ tert-Butyl 4-[4-[3-cyano- 5-[[(1R)-1-(2- pyridyl)ethyl] amino]imidazo[1,2- a]pyridin-7-yl]-5-methyl- pyrazol-1-yl]piperidine- 1-carboxylate

527.4 ¹After the mixture is cooled to RT it is concentrated under reduced pressure and purifiedby silica gel column chromatography, eluting with a gradient of DCM:MeOH (20:1). ²Prior to purification, the mixture is diluted with H₂O (30 mL), extracted with EtOAc (3 × 50 mL). The combined organic extracts are washed with brine (2 × 30 mL), driedover anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. ³Purified by silica gel column chromatography, eluting with DCM:MeOH (20:1). ⁴Purified by Prep-TLC PE:EtOAc (1:1).

Preparation 684 tert-Butyl 7-((1s,3s)-3-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate, Isomer 2

A solution of (1S,3r)-3-(4-(4-((S)-2-((tert-Butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)cyclobutan-1-ol (190 mg, 0.33 mmol) and DIPEA (214 mg, 1.66 mmol) in DCM (4.0 ml) is cooled to −78° C. is treated with (CF₃SO₂)₂O (1.40 g, 0.50 mmol). The reaction is stirred at −78° C. for 15 minutes. The reaction consequently treated with a solution of DIPEA (214 mg, 1.66 mmol) and 9-boc-3-oxa-7,9-diazabicyclo[3.3.1]nonane (151 mg, 0.66 mmol) in DCM (4 mL). The mixture is heated to 40° C. for 16 hr. Then, the reaction is cooled to RT and stirred for 2 days. The reaction is diluted with H₂O then extracted with 4:1 DCM:IPA. The layers are separated, and the organic layer is washed with H₂O, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in DCM to afford the title compound (100 mg, 38.5%) as a tan solid. ES/MS m/z 783.4 [M+H]⁺.

Preparation 685 tert-Butyl 4-[4-[3-cyano-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To tert-butyl 4-(4-[3-cyano-5-hydroxyimidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (600.00 mg, 1.42 mmol) and 2,2,2-trifluoro-1-(5-fluoropyridin-2-yl)ethyl trifluoromethanesulfonate (0.927 g, 2.83 mmol) in ACN (5.00 mL) is added K₂CO₃ (587.45 mg, 4.25 mmol) at RT under N₂. The resulting mixture is stirred at 80° C. for 3 hr. Upon cooling to RT, the aq. layer is extracted with EtOAc (3×5 mL). The combined organic layers are concentrated in vacuo. The residue is purified by reversed flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 60% ACN in water (0.1% NH₄HCO₃): UV 254 nm to afford the title compound as a white solid (450 mg, 52.88%). ES/MS m/z 601.3 [M+H]⁺.

Preparation 686 tert-Butyl 4-(4-[3-cyano-4-[2,2,2-trifluoro-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate

A stirred solution of 2,2,2-trifluoro-1-(oxan-4-yl)ethyl trifluoromethanesulfonate (204.12 mg, 0.65 mmol) and K₂CO₃ (267.64 mg, 1.94 mmol) in ACN (5.00 mL) is treated with tert-butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (300.00 mg, 0.71 mmol) at RT under N₂ and the mixture is stirred for 3 hrs at 80° C. under N₂. The solution is filtered, the filter cake is washed with DCM (2×10 mL), and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; ACN in H₂O, eluting with a gradient of 60% to 65% to give the title compound as a yellow solid (320 mg, 84.22%). ES/MS m/z 589.1 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-(4-[3-cyano-4-[2,2,2-trifluoro-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The filter cake can also be washed with EtOAc.

TABLE 48 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 687¹ tert-Butyl 4-(4-[3-cyano-4- [(1S)-2,2,2-trifluoro-1- (pyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- 1,2,3-triazol-1-yl)piperidine- 1-carboxylate

583.4 688 tert-Butyl 4-(4-(3-cyano-4- ((6,6-difluoro-6,7-dihydro- 5H-cyclopenta[b]pyridin-7- yl)oxy)pyrazolo[1,5- a]pyridin-6-yl)-5-methyl-1H- 1,2,3-triazol-1-yl)piperidine- 1-carboxylate

577.3 689² tert-Butyl 4-[4-[3-cyano-5- [(6,6-difluoro-5,7- dihydrocyclopenta[b]pyridin- 7-yl)oxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- triazol-1-yl]piperidine-1- carboxylate

577.1 ¹After stirring, the solution is cooled to RT, diluted with EtOAc (50 mL), washed with brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentratedunder reduced pressure. ²Purified by reverse phase chromatography: Column, C18; eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃).

Preparation 690 tert-Butyl 4-[4-[4-[(1R)-1-(2-cyanophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-(4-[4-[(1R)-1-(2-bromophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carboxylate (550 mg, 0.94 mmol), Zn(CN)₂ (334 mg, 2.84 mmol), Zn (62 mg, 0.95 mmol), X-Phos (226 mg, 0.47 mmol) and Pd₂(dba)₃ (434 mg, 0.47 mmol) in DMA (100 mL) is stirred overnight at 100° C. under N₂. Upon cooling to RT, the reaction is extracted with EtOAc (500 mL). The organic layer is washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by flash silica gel chromatography eluting with 10% to 100% EtOAc in PE to afford the title compound as a yellow solid (390 mg, 78%). ES/MS m/z 527.3 [M+H]⁺.

Preparation 691 tert-Butyl 4-[4-[3-cyano-4-((1S)-2,2,2-trifluoro-1-phenyl-ethoxy)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl]piperidine-1-carboxylate

tert-Butyl 4-(4-[3-cyano-4-hydroxypyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (250 mg, 590 μmol), (R)-2,2,2-trifluoro-1-phenylethan-1-ol (208 mg, 1.18 mmol), PPh₃ (310 mg, 1.18 mmol), DCM (4 ml), and di-tert-butyl (E)-diazene-1,2-dicarboxylate (299 mg, 1.30 mmol) are sequentially added together and the mixture is stirred for 2 hrs at 50° C. The mixture is concentrated and diluted with NMP. The residue is purified using prep-HPLC, eluting with a gradient of ACN:H₂O (10-90%, 0.5% HCl) to give the title compound as a white solid (94 mg, 0.14 mmol, 23%). ES/MS m/z 582.4 [M+H]⁺.

Preparation 692 tert-Butyl 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-formyl-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To ZnCl₂ (56.1 mg, 0.41 mmol) and NaH (32.9 mg, 60% wt, 0.82 mmol) in a sealed vial under N₂, tert-butyl (R)-4-(4-(3-cyano-4-(1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (150 mg, 0.27 mmol) in THF (3 mL) is added and the reaction mixture is stirred for 1.5 hr at 40° C. At this point, additional ZnCl₂ (56.1 mg, 0.41 mmol) and NaH (32.9 mg, 60% wt, 0.82 mmol) is added and continued stirring 1.5 hr at 40° C. The reaction is cooled to 0° C., silica (1.0 g) is added, diluted with hexanes (5 mL) and stirred for 1 hr at RT. The suspension is filtered, washing with EtOAc followed by 20% MeOH in DCM and concentrating in vacuo. The residue is purified by reverse phase C18 chromatography eluting with a linear gradient of 10% to 100% ACN in H₂O to afford the title compound (30 mg, 20%) as off-white solid. ES/MS 550.8 m/z [M+H]⁺.

Preparation 693 tert-Butyl 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-(hydroxymethyl)pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

NaBH₄ (2.8 mg, 0.07 Mmol) is added to a solution of tert-butyl (R)-4-(4-(4-(1-(5-fluoropyridin-2-yl)ethoxy)-3-formylpyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (20 mg, 0.04 mmol) in MeOH (3 mL) at RT. After stirring for 10 minutes the reaction is concentrated in vacuo. The residue is suspended in EtOAC and H₂O, layers are separated, and the aqueous layer is extracted with EtOAC (2×). Organic layers are combined, washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue is used in a subsequent step without additional purification. ES/MS 553.8 m/z [M+H]⁺.

Preparation 694 tert-Butyl 3-[4-[3-chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]azetidine-1-carboxylate

To tert-butyl 3-[5-methyl-4-[5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]triazol-1-yl]azetidine-1-carboxylate (200.00 mg, 0.421 mmol) in DMF (2.00 mL) is added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (41.43 mg, 0.21 mmol) at RT under N₂. The reaction is stirred at RT for 2 hr, quenched with H₂O (10 mL) and extracted with DCM (2×10 mL). The combined organic layers are washed with brine (2×10 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated in vacuo. The residue is purified by Prep-TLC (5% MeOH in DCM) to afford the title compound as a yellow solid (140 mg, 65.27%). ES/MS, m/z 510.0 [M+H]⁺.

Preparation 695 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-(4-{4-[(1R)-2-[(tert-butyldimethylsilyl)oxy]-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl}-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (770 mg, 1.22 mmol) and NCS (146 mg, 1.09 mmol) in DCM (10 mL) is stirred for 3 hr at RT under N₂. The reaction is diluted with H₂O (30 mL), extracted with DCM (3×50 mL). The combined organic layers are washed with brine (2×50 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with 50% PE in EA to afford the title compound (700 mg, 86.22%) as a light-yellow solid. %). ES/MS, m/z 668.4 [M+H]⁺.

Preparation 696 tert-Butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (1 g, 1.53 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.272 g, 1.38 mmol) in DCM (10 mL) is stirred at RT for 2 hr under N₂. The reaction is quenched with H₂O (20 mL) then extracted with DCM (2×40 mL). The combined organic layers are washed with brine (2×20 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography, eluting with PE/EtOAc (2:1-1:1) to afford the title compound as an off-white solid (460 mg, 43.69%). ES/MS m/z 686.3 [M+H]⁺.

Preparation 697 tert-Butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To tert-butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (330 mg, 0.51 mmol) in DCM (5 mL) is added NCS (64.22 mg, 0.481 mmol) at RT under N₂. The reaction is concentrated in vacuo and the residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 65% to 75% ACN in H₂O (0.1% FA) to give the title compound (185 mg, 53.25%) as a light-yellow oil. ES/MS m/z 686.0 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate.

TABLE 49 ES/MS Prep m/z No. Chemical Name Structure [[M + H]⁺ 698¹ Cis-tert-Butyl 4-[3-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]cyclobutyl]piperazine- 1-carboxylate

741.3 699² tert-Butyl 4-[4-[3- chloro-4-[2-cyano-1-(5- fluoro-2-pyridyl)-2- methyl- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carboxylate

[Cl³⁵/Cl³⁷] 553.8/555.7 (M-tBu) 700 tert-Butyl 4-[4-[4-[(1R)- 1-(5-fluoro-2- pyridyl)ethoxy]-3-iodo- pyrazolo[1,5-a]pyridin- 6-yl]-5-methyl-triazol- 1-yl]piperidine-1- carboxylate

648.4 701² tert-Butyl 4-[4-[3- bromo-4-[[(4R)-2,2- dimethyl-1,3-dioxolan- 4-yl]-(5-fluoro-2- pyridyl)methoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carboxylate

(⁷⁹Br/⁸¹Br) 685.6/ 687.6 702³ tert-Butyl 4-[4-[3- chloro-5-[(1R)-1-(5- fluoro-2- pyridyl)ethoxy]imidazo [1,2-c]pyrimidin-7-yl]-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

556.2 703³ tert-Butyl 4-[4-[5-[(1R)- 1-(5-fluoro-2- pyridyl)ethoxy]-3-iodo- imidazo[1,2- c]pyrimidin-7-yl]-5- methyl-pyrazol-1- yl]piperidine-1- carboxylate

648.2 704⁴ tert-Butyl (3R,4S)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- fluoro-piperidine-1- carboxylate, Isomer 2

704.3 705⁵ tert-Butyl (3S,4S)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- fluoro-piperidine-1- carboxylate, Isomer 2

704.2 706⁴ tert-Butyl (3S,4R)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- fluoro-piperidine-1- carboxylate, Isomer 2

704.4 707⁵ tert-Butyl (3R,4R)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- fluoro-piperidine-1- carboxylate, Isomer 2

704.4 708⁵ tert-Butyl (3S,4S)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-l-yl]-3- hydroxy-piperidine-1- carboxylate, Isomer 2

702.4 709⁵ tert-Butyl (3R,4S)-4-[4- [4-[2-[tert- butyl(dimethyl)si1yl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- m thyl-triazol-1-yl]-3- hydroxy-piperidine-1- carboxylate, Isomer 2

702.2 710⁶ tert-Butyl (3S,4R)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- hydroxy-piperidine-1- carboxylate, Isomer 2

702.4 711⁷ tert-Butyl (3R,4R)-4-[4- [4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- hydroxy-piperidine-1- carboxylate, Isomer 2

702.4 712⁵ tert-butyl (3RS,4RS)-4- [4-[4-2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carboxylate, Isomer 2

700.2 713⁵ tert-butyl (3RS,4SR)-4- [4-[4-[2-[tert- butyl(dimethyl)silyl]oxy- 1-(5-fluoro-2- pyridyl)ethoxy]-3- chloro-pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carboxylate, Isomer 2

700.2 ¹Purified by reverse phase chromatography with the following conditions: Column, C18 eluting with 70% to 80% ACN in H₂O (0.1% NH₄HCO₃). ²Purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 10% to 100% ACN in H₂O. ³Purified by silica gel chromatography, eluting with 0% to 100% EtOAc in DCM. ⁴Purified by silica gel chromatography, eluting with PE:EA (1:2). ⁵Purified by Prep-TLC PE:EA (2:1). ⁶Purified by silica gel chromatography, eluting with PE:EA (1:1:1:2). ⁷Purified by Prep-TLC PE:EA (1:1).

Preparation 714 tert-Butyl 4-[4-[3-cyano-5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-c]pyrimidin-7-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate

A solution of tert-butyl 4-[4-[5-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-iodo-imidazo[1,2-c]pyrimidin-7-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (74.0 mg, 0.11 mmol) and CuCN (11.0 mg, 0.13 mmol) in DMF (2.5 mL) is stirred at 100° C. for 1 hr. Upon cooling to RT, the reaction is quenched with aq. NH₄OH and extracted with EtOAc. The organic layer is washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0% to 100% EtOAc in DCM to afford the title compound (57 mg, 91%) as a colorless foam. ES/MS m/z 547.2 [M+H]⁺.

Preparation 715 tert-Butyl 4-[4-[3-cyano-4-[1-[2-(1-hydroxy-1-methyl-ethyl)phenyl]ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A solution of MeMgBr (178 mg, 3 molar, 1.50 mmol) in THF is added dropwise to a solution of tert-butyl 4-(4-(3-cyano-4-(1-(2-(methoxycarbonyl)phenyl)ethoxy) pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (292 mg, 0.50 mmol) in THF (3 mL) at 0° C. The reaction is stirred for 2 hr at 0° C. H₂O (3 mL) is slowly added, and the mixture is allowed warm to RT. The mixture is diluted with DCM (20 mL) and H₂O (20 mL) and the layers are separated. The aqueous layer is extracted with DCM (20 mL). The combined organic layers are concentrated in vacuo. The residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in H₂O to afford the title compound (192 mg, 65.7%). ES/MS m/z 585.8 [M+H]⁺.

Preparation of 716 2-[1-[6-[1-(1-tert-Butoxycarbonyl-4-piperidyl)-5-methyl-triazol-4-yl]-3-cyano-pyrazolo[1,5-a]pyridin-4-yl]oxyethyl]benzoic acid

To tert-butyl 4-(4-(3-cyano-4-(1-(2-(methoxycarbonyl)phenyl) ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (274 mg, 468 μmol) in THF (12 mL) is added an aq. solution of LiOH (112 mg, 4.68 mmol) and the mixture is stirred for 3 hr. The pH is adjusted to 5 using aq. HCl (0.1 M) then EtOAc (10 mL) is added. The layers are separated and the aq. phase is extracted with EtOAc (3×10 mL). The combined organics are dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (260 mg, 97.2%). ES/MS m/z 572.2 [M+H]f.

Preparation 717 tert-Butyl 4-[4-[4-[1-(2-carbamoylphenyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

To 2-(1-((6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)benzoic acid (260 mg, 455 μmol) and NH₄Cl (122 mg, 2.27 mmol) in DMF (4 mL) is added T3P (868 mg, 50% Wt, 1.36 mmol) in DMF, followed by DIEA (588 mg, 4.55 mmol) and the reaction is stirred for 3 hr. The mixture is diluted with DCM (10 mL) and H₂O (10 mL) and the layers are separated. The aq. layer is extracted with DCM (3×10 mL) and the combined organics are concentrated in vacuo. The residue is purified by reverse phase chromatography eluting with 0% to 100% ACN in H₂O to afford the title compound (80 mg, 31%). ES/MS m/z 571.3 [M+H]⁺.

Preparation 718 tert-Butyl 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-isothiazol-4-yl-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate

A mixture of tert-butyl 4-[4-[4-[(1R)-1-(5-fluoro-2-pyridyl)ethoxy]-3-iodo-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (600 mg, 0.93 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole (293 mg, 1.39 mmol), CsF (422 mg, 2.78 mmol) and Pd(DtBPF)Cl₂ (60.39 mg, 0.09 mmol) in dioxane (4 mL) is stirred for 3 hr at 60° C. under N₂. The reaction is concentrated in vacuo. The mixture is diluted with water (50 mL), extracted with EtOAc (2×50 mL). The combined organic layers are washed with brine (1×50 mL), dried over Na₂SO₄, filtered and the filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography using the following conditions: column, C18; mobile phase, eluting with a linear gradient of 30% to 50% ACN in H₂O to afford the title compound (400 mg, 71.4%) as a white solid. ES/MS m/z 605.5 [M+H]⁺.

Preparation 719 7-[1-(Azetidin-3-yl)-5-methyl-triazol-4-yl]-3-chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridine. TFA

To a stirred solution of tert-butyl 3-(4-[3-chloro-5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)azetidine-1-carboxylate (140.00 mg, 0.28 mmol) in DCM (2.00 mL) is added TFA (1.00 mL) at RT under N₂. The reaction is stirred 1 hr at RT then concentrated in vacuo to afford the title compound (120 mg, crude) as a yellow solid, which is carried forward without a further purification. ES/MS m/z 410.0 [M+H]⁺.

Preparation 720 4-[1-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. HCl

A mixture of tert-butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-cyano-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (2.7 g, 4.00 mmol) in DCM (50 ml) and 4M HCl in 1,4-dioxane (25 mL) is stirred for 1 hr at RT under N₂. The resulting mixture is concentrated in vacuo to give the title compound (2.3 g, crude, HCl salt), which is carried forward without a further purification. ES/MS m/z 462.2 [M+H]⁺.

Preparation 721 2-[3-Chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol. HCl

A solution of tert-butyl 4-[4-[4-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (175 mg, 0.26 mmol) in DCM (3 mL) and 4M HCl in 1,4-dioxane (1.5 mL) is stirred at RT for 1 hr under N₂. The resulting mixture is concentrated in vacuo to give the title compound (165 mg) which is carried forward without a further purification. ES/MS m/z 472.2 [M+H]⁺.

Preparation 722 2-[3-Chloro-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridin-5-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol. HCl

To tert-butyl 4-[4-[5-[2-[tert-butyl(dimethyl)silyl]oxy-1-(5-fluoro-2-pyridyl)ethoxy]-3-chloro-imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (450 mg, 0.66 mmol) in DCM (4 mL) is added 4M HCl in 1,4-dioxane (4 mL). After stirring 1 hr at RT the reaction is concentrated in vacuo to afford the title compound (300 mg, HCl salt) which is carried forward without a further purification. ES/MS m/z 472.2 [M+H]⁺.

The following compounds are prepared essentially as described for 2-[3-Chloro-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridin-5-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol HCl using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 50 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 723 4-[1-(5-Fluoro-2-pyridyl)-3- hydroxy-propoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

477.4 724 5-[2-Hydroxy-1-[5- (trifluoromethyl)-3- pyridyflethoxy]-7-[5-methyl- 1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile. HCl

513.3 725 5-[1-(3,5-Difluoro-2- pyridyl)-2-hydroxy-ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile. HCl

481.1 726 7-[1-(7-Azaspiro[3.5]nonan- 2-yl)-5-methyl-triazol-4-yl]- 5-[1-(5-fluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. HCl

503.3 727 4-[1-(5-Fluoro-2-pyridyl)-2- hydroxy-ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

463.1 728 4-[2-Hydroxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

513.3 729 5-[1-(5-Fluoro-2-pyridyl)-3- hydroxy-propoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile. HCl

477.2 730 6-[1-(7-Azaspiro[3.5]nonan- 2-yl)-5-methyl-pyrazol-4- yl]-4-[1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

502.3 731 2-[3-Fluoro-6-[5-methyl-1- (4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl

456.2 732 2-[3-Chloro-6-[5-methyl-1- (4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(2-pyridyl)ethanol HCl

454.2 733 4-[1-[2-(3-Hydroxyazetidin- 1-yl)-5-(trifluoromethyl)-3- pyridyl]ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile HCl

568.2 734 2-[3-Chloro-6-[1-[(3R,4S)- 3-fluoro-4-piperidyl]-5- methyl-triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl, Isomer 2

490.2 735 2-[3-Chloro-6-[1-[(3S,4S)-3- fluoro-4-piperidyl]-5- methyl-triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl, Isomer 2

490.2 736 2-[3-Chloro-6-[1-[(3S,4R)- 3-fluoro-4-piperidyl]-5- methyl-triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl, Isomer 2

490.2 737 2-[3-Chloro-6-[1-[(3R,4R)- 3-fluoro-4-piperidyl]-5- methyl-triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl, Isomer 2

490.1 738 (3S,4S)-4-[4-[3-Chloro-4-[1- (5-fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidin-3-ol HCl, Isomer 2

488.2 739 (3R,4S)-4-[4-[3-chloro-4-[1- (5-fluoro-2-pyridyl)-2- hydroxy-ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidin-3-ol HCl, Isomer 2

488.2 740 (3S,4R)-4-[4-[3-Chloro-4- [1-(5-fluoro-2-pyridyl)-2- hydroxy-ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidin-3-ol HCl, Isomer 2

488.1 741 (3R,4R)-4-[4-[3-Chloro-4- [1-(5-fluoro-2-pyridyl)-2- hydroxy-ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidin-3-ol HCl, Isomer 2

488.2 743 2-[3-Chloro-6-[5-Methyl-1- [(3RS,4SR)-3-methyl-4- piperidyl]triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl

486.2 744 Cis-2-[3-Chloro-6-[5- methyl-1-(3-piperazin-1- ylcyclobutyl)triazol-4- yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl

527.2 745 4-[2-Hydroxy-1-(4- isoquinolyl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile HCl

495.2

Preparation 746 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile. HCl

To a stirred solution of tert-butyl 4-[4-[3-cyano-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (450.00 mg, 0.75 mmol) in DCM (5.00 mL) is added 4M HCl in 1,4-dioxane (2 mL) at RT under N₂. The resulting mixture is stirred at RT for 1 hr, then is concentrated in vacuo to afford the title compound (300 mg). The title compound is carried forward without a further purification. ES/MS m/z 501.2 [M+H]⁺.

Preparation 747 5-Methoxy-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl

A solution of tert-butyl 4-(4-[3-ethynyl-5-methoxyimidazo[1,2-a]271yridine-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (450.00 mg, 1.03 mmol), DCM (10 mL), and HCl (4 M) in 1,4-dioxane (10.00 mL) is stirred for 2 hrs at RT. The mixture is concentrated under reduced pressure, diluted with EtOAc (3 mL) and hexanes (20 mL), and stirred 5 min. The solid is collected by filtration, and the filter cake is washed with hexanes (2×10 mL) and lyophilized to give the title compound as a brown solid (110 mg, 28.6%). ES/MS m/z 338.0 [M+H]⁺.

Preparation 748 4-Isopropoxy-6-[5-methyl-1-[piperidin-4-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

tert-Butyl 4-[4-(3-cyano-4-isopropoxy-pyrazolo[1,5-a]271yridine-6-yl)-5-methyl-pyrazol-1-yl]piperidine-1-carboxylate (75 mg, 0.16 mmol) is stirred at RT in TFA (1 mL) for 30 min. The mixture is concentrated to dryness to give the title compound (54.2 mg, 92.12%) which is used without further purification. ES/MS m/z 365.2 [M+H]⁺

The following compounds are prepared essentially as described for 4-isopropoxy-6-[5-methyl-1-[piperidin-4-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. Temperature is varied from RT to 50° C. The mixture can also be quenched with saturated Na₂CO₃ aq and extracted with EtOAc. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 51 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 749¹ 4-Methoxy-6-[5-methyl-1- [(3S)-piperidin-3- yl]pyrazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile.FA

337.20 750 6-[5-Methyl-1-(4- piperidyl)pyrazol-4-yl]-4- [1-(2- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, TFA

505.2 751 5-[1-(1,3-Benzothiazol-7- yl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. TFA

485.1 752 6-[1-[1-(6- Azabicyclo[3.2.1]octan-3- yl)azetidin-3-yl]-5-methyl- pyrazol-4-yl]-4-methoxy- pyrazolo[1,5-a]pyridine-3- carbonitrile. TFA

418.2 753 7-[1-(Azetidin-3-yl)-5- methyl-pyrazol-4-yl]-5- [(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. TFA

400.0 754 7-[1-(Azepan-4-yl)-5- methyl-triazol-4-yl]-5- [(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. TFA

443.2 755 5-[[(1R)-1-(5-Fluoro-2- pyridyl)ethyl]amino]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. TFA

446.2 756 5-[(5-Fluoro-2- pyridyl)methoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. 2 TFA

433.2 ¹Reverse Combi-flash chromatography with the following conditions: C18; eluting with a gradient of 50-70% ACN in H₂O (0.1% FA).

Preparation 757 6-[1-(Azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.FA

A solution of tert-butyl 3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]273yridine-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carboxylate (480 mg, 1.18 mmol) and TFA (20 mL) in DCM (20 mL) is stirred for 30 min at RT under N₂. The mixture is concentrated under reduced pressure. The pH of the residue is adjusted to pH 8 with aq., sat'd. NaHCO₃ and extracted with DCM:iPrOH (3:1) (3×100 mL). The combined organic extracts are washed with brine (1×10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 0% to 30% ACN in H₂O (0.1% FA), to give the title compound as a white solid (210 mg, 57%). ES/MS m/z 309.05 [M+H]⁺.

Preparation 758 5-[(1R)-1-(5-Fluoropyridin-2-yl)ethoxy]-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl

A stirred solution of tert-butyl 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]274yridine-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (70.0 mg, 0.128 mmol) in DCM (3.0 mL) is treated with 4 M HCl in 1,4-dioxane (1.0 mL) and stirred for 30 min at RT under N₂. The mixture is concentrated under reduced pressure and washed with EtOAc (3×20 mL) to give the title compound as a yellow solid (95 mg, crude). ES/MS m/z 447.2 [M+H]⁺.

Preparation 759 6-[5-Methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]-4-[(1R)-1-(274yridine-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile.TFA

A solution of tert-butyl 4-(4-[3-cyano-4-[(1R)-1-(274yridine-2-yl)ethoxy]pyrazolo[1,5-a]274yridine-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (354 mg, 0.67 mmol) and TFA (1 mL) is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure, and the residue is purified by trituration with MTBE (5 mL). The precipitated solids are collected by filtration and washed with MTBE (2×2 mL) to give the title compound as a brown solid (456 mg), which is used directly without further purification. ES/MS m/z 429.3 [M+H]⁺.

Preparation 760 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethylamino]imidazo[1,2-a]pyridine-3-carbonitrile. TFA

A solution of tert-butyl 4-[4-[3-cyano-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]275yridine-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (150.00 mg, 0.251 mmol), TFA (5 mL) and DCM (10 mL) is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure to give the title compound. ES+H, m/z 497.3 [M+H]⁺.

Preparation 761 5-[1-(5-Fluoro-2-pyridyl)-2-methoxy-ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.TFA

A mixture of tert-butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]275yridine-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (150.00 mg, 0.26 mmol) in TFA (2.00 mL) and DCM (4.00 mL) is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure to give the title compound which is used directly without further purification (140 mg). ES/MS m/z 477.2 [M+H]⁺.

Preparation 762 5-[1-(5-Fluoro-2-pyridyl)propoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl

A mixture of (200.00 mg, 0.36 mmol) tert-butyl 4-[4-[3-cyano-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridine-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate in 4 M HCl (gas) in 1,4-dioxane (2.00 mL) and DCM (3.00 mL) is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure to give the title compound (200 mg) which is used directly without further purification. ES/MS m/z 461.3 [M+H]⁺.

Preparation 763 4-[1-(5-Fluoro-2-pyridyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl

A mixture of tert-butyl 4-[4-[3-cyano-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carboxylate (180.00 mg, 0.31 mmol) in 4 M HCl (gas) in 1,4-dioxane (2.00 mL) and DCM (4.00 mL) is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure to give the title compound (160 mg) which is used directly without further purification. ES/MS m/z 477.2 [M+H]⁺.

The following compounds are prepared essentially as described for 4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. TFA and trifluoroacetaldehyde can be substituted for HCl. The precipitated solids can also be triturated with Et₂O and DCM. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 52 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 764 6-[1-(Azetidin-3-yl)-5- methyl-1,2,3-triazol-4-yl]- 4-[(1R)-1-(pyridine-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile. TFA

400.1 765 6-[1-(Azetidin-3- yl)pyrazol-4-yl]-4- methoxypyrazolo[1,5- a]pyridine-3- carbonitrile. TFA

295.2 766 6-[5-Methyl-1-(piperidin- 4-yl)pyrazol-4-yl]-4- [(1R)-1-(pyrazin-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

429.2 767 6-[5-Methyl-1-(piperidin- 4-yl)pyrazol-4-yl]-4- [(1R)-1-(277yridine-2- yl)propoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

442.4 768 4-[(1R)-1- Cyclobutylethoxy]-6-[5- methyl-1-(piperidin-4-yl)- 1,2,3-triazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

406.3 769 4-Methoxy-6-(5-methyl-1- ((3S,5R)-5- methylpyrrolidin-3 -yl)- 1H-pyrazol-4- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

337.2 770 4-Methoxy-6-[5-methyl-1- [(3S,5S)-5- methylpyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

337.1 771 6-[1-(5,5- Dimethylpyrrolidin-3 -yl)- 5-methylpyrazol-4-yl]-4- methoxypyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

351.2 772 6-[5-Methyl-1-(piperidin- 4-yl)pyrazol-4-yl]-4- [2,2,2-trifluoro-1-(oxan-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

489.1 773 6-[5-Methyl-1-[(3S)- pyrrolidin-3-yl]pyrazol-4- yl]-4-[[(1R)-1- (278yridine-2- yl)ethyl]amino]pyrazolo [1,5-a]pyridine-3- carbonitrile. HCl

413.1 774 4-[2-methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

527.2 775 5-[1-(5-Fluoro-2-pyridyl)- 2-hydroxy-ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. HCl

463.1 776 5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)pyrazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. HCl

446.4 777 3-Chloro-5-[(1R)-1-(5- fluoro-2-pyridyl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine. TFA

456.1 778 7-[1-(7- Azaspiro[3.5]nonan-2-yl)- 5-methyl-triazol-4-yl]-5- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo[1, 2-a]pyridine-3-carbonitrile HCl

487.2 779 4-[2-fluoro-1-(5-fluoro-2- pyridyl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile Di-HCl

464.8 780 7-[5-methyl-1-(4- piperidyl)triazol-4-yl]-5- [(1R)-1-(2- pyridyl)propoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2 TFA

442.9 781 4-[cyclopropyl-(5-fluoro- 2-pyridyl)methoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile TFA

a 782 4-[(1-fluorocyclopropyl)- (5-fluoro-2- pyridyl)methoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile TFA

492.8 783 4-[(5-fluoro-2-pyridyl)-[1- (trifluoromethyl)cyclopropyl] methoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

541.1 784 5-[2-Cyclopropyl-1-(2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

469.2 785 5-[(1R)-1-(3-Fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

447.2 786 5-[(6,6-Dimethyl-5,7- dihydrocyclopenta[b]pyridin- 7-yl)oxy]-7-[5-methyl- 1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

469.2 787 5-[1-(3,5-Difluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

464.8 788 6-[1-(3,3-Difluoro-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-methoxy- pyrazolo[1,5-a]pyridine-3- carbonitrile HCl

373.3 789 5-(1-Isothiazol-3- ylethoxy)-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

435.10 790 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-4- [1-[5-(trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1- ,5-a]pyridine-3- carbonitrile HCl

497.1 791 2-[(1R)-1-[6-[5-Methyl-1- (4-piperidyl)pyrazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxyethyl]benzonitrile HCl

427.2 792 7-[1-(7- Azaspiro[3.5]nonan-2-yl)- 5-methyl-triazol-4-yl]-5- [(1R)-1-(2-pyridyl) ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

469.3 793 6-[1-(3,3-Difluoro-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-methoxy- pyrazolo[1,5-a]pyridine-3- carbonitrile HCl

373.3 794 5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-[(3S)-3- piperidyl]triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

447.1 795 5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-[(3R)-3- piperidyl]triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

447.2 796 7-[5-Methyl-1-(4- piperidyl)pyrazol-4-yl]-5- [[(1R)-1-(2-pyridyl)ethyl] amino]imidazo[1,2- a]pyridine-3-carbonitrile HCl

427.1 797 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5- [(1R)-1-pyrimidin-4- ylethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

430.2 798 5-[1-(6-Chloro-3- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

a 799 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5- (trifluoromethyl)isoxazol- 3-yl]ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

487.2 800 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-4- [1-(5-methyl-1,3,4- thiadiazol-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

450.1 801 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-4- [1-[2-morpholino-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile 2 HCl

582.3 802 5-[1-(1-Isopropyltriazol-4- yl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

461.2 803 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5- [1-(6-methylpyrazin-2- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile 2 HCl

444.2 804 5-[1-(3,3- Difluorocyclobutyl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

442.2 805 5-[(1R)-1-(2-Chloro-4- fluoro-phenyl)ethoxy]-7- [5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

479.2 [M]⁺ 806 5-[(1R)-1-(5-Fluoro-3- methyl-2-pyridyl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

461.1 807 5-[2,2-Difluoro-1-(5- fluoro-2-pyridyl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile di-HCl

483.2 808 5-[(5-Fluoro-2-pyridyl)- (trifluoromethyl)cyclopropyl] methoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

541.2 809 5-[2-Methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

527.1 810 5-[1-(5-Fluoro-3- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

447.3 811 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5- [(1R)-1-(5-methyl-1,3,4- thiadiazol-2- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

450.1 812 4-[1-(4-methylisothiazol- 5-yl)ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

449.20 813 4-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

447.2 814 4-[2-methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

527.2 815 5-[(6,6-Difluoro-5,7- dihydrocyclopenta[b]pyridin- 7-yl)oxy]-7-[5-methyl- 1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

477.1 816 5-[1-(5-Chloropyridazin- 3-yl)ethoxy]-7-[5-methyl- 1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. HCl

464.1 817 4-[1-(5-Chloropyridazin- 3-yl)ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

464.1 818 7-[5-Methyl-1-(4 piperidyl)triazol-4-yl]-5- [1-(5-methyl-3- pyridyl)ethoxy]imidazo[1, 2-a]pyridine-3- carbonitrile. HCl

443.2 819 5-[1-[5-(Difluoromethyl)- 3-pyridyl]ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile. HCl

479.1 820 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-4- [1-(6-methylpyrazin-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. 2 HCl

444.2 821 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-4- [1-(5-methylthiazol-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

449.2 822 2-[3-Fluoro-6-[5-methyl- 1-(4-piperidyl)triazol-4 yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-1-(5-fluoro-2- pyridyl)ethanol HCl

456.2 823 2-[3-Chloro-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-1-(5-fluoro-2- pyridyl)ethanol HCl

472.2 824 1-[3-Chloro-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-2-(5-fluoro-2- pyridyl)propan-2-ol HCl

486.2 825 1-[3-Fluoro-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-2-(5-fluoro-2- pyridyl)propan-2-ol HCl

470.2 826 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5- [(1R)-1-[4-(2,2,2- trifluoroethyl)-1,2,4- triazol-3- yflethoxy]imidazo[1,2- a]pyridine-3-carbonitrile TFA

501.2 827 2-[3-Fluoro-6-[5-methyl- 1-(4-methyl-4- piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-2-(5-fluoro-2- pyridyl)ethanol HCl, Isomer 2

470.2 828 3-Cyclopropyl-4-[(1R)-1- (5-fluoro-2- pyridyl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine HCl

461.9 829 4-[1-[2-(1-Hydroxy-1- methyl- ethyl)phenyl]ethoxy]-6- [5-methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

485.9 830 3-[3-Chloro-6-[5-methyl- 1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin- 4-yl]oxy-3-(5-fluoro-2- pyridyl)-2,2-dimethyl- propanenitrile 2HCl

481.7 [M − 2H − CN]⁺ 831 4-[1-[2-(2- Methoxyethylamino)-5- (trifluoromethyl)-3- pyridyl]ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile 2HCl

570.2 821 5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-743-(2- hydroxyethyl)-5-methyl- 1-(4-piperidyl)pyrazol-4- yl]imidazo[1,2-a]pyridine- 3-carbonitrile HCl

490.3 a Material taken on to next step without further purifcation.

Preparation 833 4-Methoxy-6-(5-methyl-1-[1-[(3S)-pyrrolidin-3-yl]pyridine289-3-yl]pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of tert-butyl (3S)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]289yridine-6-yl]-5-methylpyrazol-1-yl pyridine289-1-yl]pyrrolidine-1-carboxylate (190 mg, 0.42 mmol) in TFA (5 mL) and DCM (5 mL) is stirred for 2 hrs at RT. The mixture is concentrated under reduced pressure to give the title compound as a dark green oil (260 mg). The pH of the crude product (60 mg) is adjusted with NaHCO₃ and purified by Prep-HPLC with the following conditions: Column, Xbridge Shield RP18 OBD, 19*150 mm, 5 μm; eluting with a gradient of 20% to 35% ACN in H₂O (10 mmol/L NH₄HCO₃), flow rate: 25 mL/min; 254 nm; t_((R)) 5.57 min to give the title compound as a white solid (20 mg, 12.7%). ES/MS m/z 378.3 [M+H]⁺.

The following compounds are prepared essentially as described for (S)-4-methoxy 6-(5-methyl-1-[1-[(3S)-pyrrolidin-3-yl]pyridine289-3-yl]pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The crude product can also be dissolved in MeOH and Na₂CO₃ can also be used as an alternate base. 2,6-Lutidine in DCM can also be used as the base and solvent combination. HCl in 1,4-dioxane can also be used in lieu of TFA. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 53 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 834¹ 4-Methoxy-6-[5- methyl-1-[1-[(3S)-3- piperidyl]pyridine-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

392.05 835² 4-Methoxy-6-[5- methyl-1-[1-[(3R)-3- piperidyl]pyridine-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

392.20 836³ 4-[1-(2-Ethyltriazol-4- yl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

447.2  837³ 4-[(1- fluorocyclopropyl)-(5- fluoro-2- pyridyl)methoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

492.8  838⁴ 5-[1-(5-Chloro-2- pyridyl)-2-hydroxy- ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile

479.1  839^(5,6,7) 4-methoxy-6-(4- methyl-5-piperazin-1- yl-1,2,4-triazol-3- yl)pyrazolo[1,5- a]pyridine-3- carbonitrile

339.2  840⁸ 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]- 4-[(1R)-1-(2- methylthiazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile

449.2  841⁸ 6-[5-Methyl-1-(4- piperidyl)triazol-4-yl]- 4-[(1R)-1-(1- methylpyrazol-3- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile

432.2  842⁹ 5-[1-(1,2-Benzothiazol- 7-yl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile

485.1  843⁹ 4-[1-(1,2-Benzothiazol- 7-yl)ethoxy]-6-[5- methyl-1-(4- piperidyl)triazol-4- yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

485.2  844¹⁰ 5-[(1R)-1-(4- Fluorophenyl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile

446.2  845¹¹ 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]- 5-[1-(5- methylpyridazin-3- yl)ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

444.2  846¹² 3-Chloro-5-[(1R)-1-(5- fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)pyrazol-4- yl]imidazo[1,2- c]pyrimidine

439.2  ¹Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD, 19 * 150 mm, 5 μm; eluting with 38-50% MeOH in H₂O (0.05% NH₃H₂O). ²Reverse Combi-flash chromatography with the following conditions: Column, C18, eluting with a gradient of 30-60% ACN in H₂O (0.1% NH₃H₂O). ³Reverse phase chromatography eluting with a gradient of 0-100% ACN in H₂O. ⁴Purified by reverse flash chromatography: Column, C18; eluting with 50% to 55% ACN in H₂O (0.1% NH₄OH), 50% to 55% gradient. ⁵Reaction is diluted with 3:1 CHCl₃:iPrOH and concentrated in vacuo. Residue is dissolved into 4:1 DCM:iPrOH, washed with NaHCO₃, washed with H₂O, brine, dried over Na₂SO₄, filtered and concentrated. ⁶Reverse phase C18 chromatography eluting with 10% to 95% ACN in H₂O. ⁷Reverse phase C18 chromatography eluting with 10% to 100% ACN in H₂O. ⁸Volatiles are removed, and residue is filtered through a carbonate cartridge. ⁹The reaction is quenched by the addition of aq NaHCO₃, and the mixture is extracted with DCM. ¹⁰Purified by reverse phase chromatography: Column, C18; eluting with 50% to 60% ACN in H₂O (0.1% NH₄HCO₃). ¹¹Purified by reverse phase chromatography: Column, C18; eluting with 0% to 50% ACN in H₂O (0.1% FA). ¹²Reaction concentrated in vacuo. Residue is dissolved into 3:1 CHCl₃:IPA, washed with aq NaHCO₃, H₂O, brine, dried over Na₂SO₄, filtered and concentrated.

Preparation 847 5-Methoxy-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl

A solution of tert-butyl 4-(4-[3-ethynyl-5-methoxyimidazo[1,2-a]pyridine-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (450.00 mg, 1.03 mmol), DCM (10 mL), HCl (4 M) in 1,4-dioxane (10.00 mL) is stirred for 2 hrs at RT. The mixture is concentrated under reduced pressure, diluted with EtOAc (3 mL) and hexanes (20 mL), and stirred 5 min. The solid is collected by filtration, and the filter cake is washed with hexanes (2×10 mL) and lyophilized to give the title compound as a brown solid (110 mg, 28.6%). ES/MS m/z 338.0 [M+H]⁺.

Preparation 848 6-[1-[1-(Azetidin-3-yl)piperidin-4-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile

TFA (2 mL) is added dropwise to a stirred solution of tert-butyl 3-[4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)piperidin-1-yl]azetidine-1-carboxylate (100.00 mg, 0.20 mmol) in DCM (2.00 mL) and the solution is stirred for 1 hr at RT. The mixture is concentrated under reduced pressure to give the title compound (120 mg, crude). The product is used directly without further purification. ES/MS m/z 392.2 [M+H]⁺.

The following compounds are prepared essentially as described for 6-[1-[1-(azetidin-3-yl)piperidin-4-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions. 2,6-Lutidine in DCM can also be used as the solvent. HCl in 1,4-dioxane or TMSOTf can also be used in lieu of TFA. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 54 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 849 4-Methoxy-6-(5-methyl-1-[1-[(3R)-pyrrolidin-3- yl]pyridine-3-yl]pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

378.2 850¹ 6-[1-(Azetidin-3-yl)-5-methyl-1,2,3-triazol-4-yl]-4- methoxypyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

310.2 851 4-Methoxy-6-[5-methyl-1-(piperidin-4-yl)-1,2,3- triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

338.1 852² 4-Methoxy-6-(5-methyl-1-(7-azaspiro[3.5]nonan-2- yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carbonitrile. HCl

377.3 853 6-[1-(Azetidin-3-yl)-5-methyl-1,2,3-triazol-4-yl]-4- isopropoxypyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

338.2 854³ 6-(1-((1R,3r,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-5- methyl-1H-pyrazol-4-yl)-4-methoxypyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

363.2 855⁴ 6-(1-((1R,3s,5S)-8-Azabicyclo[3.2.1]octan-3-yl)-5- methyl-1H-pyrazol-4-yl)-4-methoxypyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

 363.15 856 4-Methoxy-6-(5-methyl-1-(1-((3S)-pyrrolidin-3- yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

406.1 857 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

428.3 858 6-[1-(Azetidin-3-yl)-5-methylpyrazol-4-yl]-4- [(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

400.2 859 4-Methoxy-6-(5-methyl-1-[1-[(3R)-pyrrolidin-3- yl]piperidin-4-yl]pyrazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

406.1 860 6-[1-[(4S)-Azepan-4-yl]-5-methylpyrazol-4-yl]-4- methoxypyrazolo[1,5-a]pyridine-3-carbonitrile. HCl

351.3 861⁵ 6-[1-[(4R)-Azepan-4-yl]-5-methylpyrazol-4-yl]-4- methoxypyrazolo[1,5-a]pyridine-3-carbonitrile. HCl

351.2 862 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [(1S)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. TFA

428.2 863 6-(5-Methyl-1-[1-[(3S)-pyrrolidin-3-yl]azetidin-3- yl]pyrazol-4-yl)-4-[(1R)-1-(pyridin-2- yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

469.3 864 6-(5-Methyl-1-[1-[(3R)-pyrrolidin-3-yl]azetidin-3- yl]pyrazol-4-yl)-4-[(1R)-1-(pyridin-2- yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

469.2 865 6-(1-(Azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4- methoxypyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

309.3 866⁶ 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [(1R)-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

435.4 867 4-[(3-Fluoropyridin-2-yl)methoxy]-6-[5-methyl-1- (piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

432.2 868⁴ 4-[(1R)-1-(3-Fluoropyridin-2-yl)ethoxy]-6-[5- methyl-1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

446.3 869 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [(1R)-1-(2-methylpyrazol-3- yl)ethoxy]pyrazolo[1,5-a]pyridine-3- carbonitrile. HCl

431.2 870 7-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-5- [(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. TFA

428.3 871 4-Methoxy-6-(5-methyl-1-[1-[(3R,5S)-5- methylpyrrolidin-3-yl]azetidin-3-yl]pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

392.1 872 4-Methoxy-6-(5-methyl-1-((3R,5S)-5- methylpyrrolidin-3-yl)-1H-pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

337.2 873 4-Methoxy-6-[1-[1-(5,5-Dimethylpyrrolidin-3- yl)azetidin-3-yl]-5-methylpyrazol-4-yl]- pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

406.1 874 4-Methoxy-6-(5-methyl-1-[1-[(3R,5R)-5- methylpyrrolidin-3-yl]azetidin-3-yl]pyrazol-4- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

392.2 875 4-Methoxy-6-[5-methyl-1-[(3R,5R)-5- methylpyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

 337.10 876 4-[(1R)-1-Cyclopropylethoxy]-6-[5-methyl-1- (piperidin-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile

392.1 877 4-[(1R)-1-Cyclopropylethoxy]-6-[5-methyl-1- (piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile

391.3 878⁷ 6-[5-Methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]- 4-[(1R)-1-phenylethoxy]pyrazolo[1,5-a]pyridine-3- carbonitrile

428.1 879 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [[(2S)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

419.4 880 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4- [[(2R)-1,1,1-trifluoropropan-2-yl]oxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

419.2 881 7-[5-Methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]- 5-[(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. TFA

429.2 882 4-[[(7R)-6,7-dihydro-5H-cyclopenta[b]pyridin-7- yl]oxy]-6-[5-methyl-1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. HCl

441.3 883 4-[(1R)-1-Cyclohexylethoxy]-6-[5-methyl-1- (piperidin-4-yl)-1,2,3-triazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile

434.4 884 6-[5-Methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]- 4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5- a]pyridine-3-carbonitrile

413.2 885 6-(5-Methyl-1-(1-((3R)-pyrrolidin-3-yl)azetidin-3- yl)-1H-pyrazol-4-yl)-4-(((R)-1-(pyridin-2- yl)ethyl)amino)pyrazolo[1,5-a]pyridine-3- carbonitrile

468.4 886 2-[(1R)-1-([3-Chloro-7-[5-methyl-1-(piperidin-4- yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]300yridine-5- yl]oxy)ethyl]pyridine. TFA

438.2 887⁸ 6-[5-Methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4-[[2- (300yridine-2-yl)propan-2-yl]oxy]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

442.3 888 6-[5-Methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]- 4-[(1S)-2,2,2-trifluoro-1-(300yridine-2- yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

483.4 889⁹ 6-(1-[1-[3,3-Difluoropiperidin-4-yl]azetidin-3-yl]- 5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5- a]pyridine-3-carbonitrile. TFA, Isomer 1

428.0 890⁹ 6-(1-[1-[3,3-Difluoropiperidin-4-yl]azetidin-3-yl]- 5-methylpyrazol-4-yl)-4-methoxypyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

428.1 891 4-((6,6-Difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-7-yl)oxy)-6-(5-methyl-1- (piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

477.2 892 7-[1-(Azetidin-3-yl)-5-methyl-1,2,3-triazol-4-yl]-5- [(1R)-1-(pyridin-2-yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile. TFA

401.2 893 4-[(1R)-1-Cyclobutylethoxy]-6-[5-methyl-1- (piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5- a]pyridine-3-carbonitrile. HCl

405.3 894¹⁰ 4-Methoxy-6-[5-methyl-1-[(3S)-pyrrolidin-3-yl]- 1,2,3-triazol-4-yl]pyrazolo[1,5-a]pyridine-3- carbonitrile. HCl

 323.95 895 4-((1S)-2,2,2-trifluoro-1-phenyl-ethoxy)-6-[5- Methyl-1-(piperidin-4-yl)-1,2,3-triazol-4- yl]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

482.4 896 6-[5-Methyl-1-(4-piperidyl)pyrazol-4-yl]-4-[[(1R)- 1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridine- 3-carbonitrile TFA

427.2 897 5-[2,2-Dimethyl-1-(2-pyridyl)propoxy]-7-[5- methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2- a]pyridine-3-carbonitrile HCl, Isomer 1

471.1 898 5-[[(7R)-6,7-Dihydro-5H-cyclopenta[b]pyridin-7- yl]oxy]-7-[5-methyl-1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3-carbonitrile HCl

441.3 899 4-[1-(4-Isoquinolyl)ethoxy]-6-[5-methyl-1-(4- piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3- carbonitrile HCl

479.2 900 4-[1-(7-Fluoro-4-isoquinolyl)ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile HCl

497.2 901 6-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-4-[1-(5- methylpyridazin-3-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile HCl

444.2 902 2-[1-[3-cyano-6-[5-methyl-1-(4-piperidyl)triazol-4- yl]pyrazolo[1,5-a]pyridin-4-yl]oxyethyl]benzamide TFA

471.2 903 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[2- pyridyl-[1- (trifluoromethyl)cyclopropyl]methoxy]imidazo[1,2- a]pyridine-3-carbonitrile TFA

523.2 904 7-[5-methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-(5- methyl-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3- carbonitrile TFA

443.1 905 6-[5-Methyl-1-[1-[(3S)-pyrrolidin-3-yl]azetidin-3- yl]pyrazol-4-yl]-4-[[(1R)-1-(2- pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridine-3- carbonitrile TFA

468.1 906 4-[1-(1-Isopropyltriazol-4-yl)ethoxy]-6-[5-methyl- 1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile Di-HCl

461.2 907 6-[5-Methyl-1-(4-piperidyl)pyrazol-4-yl]-4-[1-(3- methylsulfonylphenyl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile TFA

505.2 908 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-(3- methylsulfonylphenyl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile TFA

506.2 909 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-(5- methylthiazol-2-yl)ethoxy]imidazo[1,2-a]pyridine- 3-carbonitrile TFA

449.3 910 5-[(1R)-1-(5-Fluoro-2-pyridyl)ethoxy]-3-methyl-7- [5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2- a]pyridine TFA

436.2 911 6-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-4-[1-(1- methylpyrrolo[2,3-c]pyridin-4- yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile. TFA

482.2 912 4-Methoxy-6-[5-methyl-1-(4-piperidyl)pyrazol-4- yl]-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine TFA

379.9 913 4-[4-[(1R)-1-(5-Fluoro-2-pyridyl)ethoxy]-6-[5- methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5- a]pyridin-3-yl]isothiazole HCl

505.3 914 [4-[(1R)-1-(5-Fluoro-2-pyridyl)ethoxy]-6-[5- methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5- a]pyridin-3-yl]methanol HCl

 434.90 [M + H − H2O]⁺ 915 5-[1-(5-Fluoro-2-pyridyl)-2- (trifluoromethoxy)ethoxy]-7-[5-methyl-1-(4- piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3- carbonitrile HCl

531.2 916 5-[1-[5-Fluoro-6-(2-methoxyethoxy)-2- pyridyl]ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol- 4-yl]imidazo[1,2-a]pyridine-3-carbonitrile HCl

521.2 917 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-[5- (trifluoromethoxy)-3-pyridyl]ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

513.2 918 7-[1-[(2SR,4RS)-2-Cyclopropyl-4-piperidyl]-5- methyl-triazol-4-yl]-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2-a]pyridine-3- carbonitrile HCl

469.2 919 (2R)-3-[3-Bromo-6-[5-methyl-1-(4- piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4- yl]oxy-3-(5-fluoro-2-pyridyl)propane-1,2-diol HCl

(⁷⁹Br/⁸¹Br)  545.7/ 547.7 920 7-[5-Methyl-1-(2-methyl-2-piperazin-1-yl- propyl)triazol-4-yl]-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2-a]pyridine-3- carbonitrile HCl

486.3 921¹¹ 2-((6-(1-((1s,3s)-3-(3-oxa-7,9- diazabicyclo[3.3.1]nonan-7-yl)cyclobutyl)-5- methyl-1H-1,2,3-triazol-4-yl)-3- chloropyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5- fluoropyridin-2-yl)ethan-1-ol, 2 HCl, Isomer 2

569.2 922¹² 6-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-4-[1-(2- methyltriazol-4-yl)ethoxy]pyrazolo[1,5-a]pyridine- 3-carbonitrile

433.2 ¹Crude product is re-crystallized from EtOAc:PE (40:40 mL). ²Purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 20-30% ACN in H₂O (0.1% HCl). ³The crude product is re-crystallized from EtOAc. ⁴Mixture is filtered, and the filter cake washed with EtOAc. ⁵Crude product is triturated with DCM. ⁶Crude product is concentrated and re-crystallized from EtOAc:MTBE. ⁷The reaction is quenched by the addition of sat. NH₄Cl (10.0 mL) at RT and the mixture is extracted with CHCl₃ and iPrOH (3:1, 3 × 30 mL). ⁸Crude product is triturated in MTBE:EtOAc (5:1) and collected by filtration. ⁹Mixture is washed with Et₂O. ¹⁰The crude product is re-crystallized from MeOH/EtOAc. ¹¹Reaction is diluted with MTBE and filtered to collect pale yellow solid as the title compound. ¹²Reverse phase chromatography eluting with a gradient of 0-100% ACN in H₂O.

Preparation 923 5-[(1R)-1-(2-Fluorophenyl)ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile

To a solution of tert-butyl 4-(4-[3-cyano-5-[(1R)-1-(2-fluorophenyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carboxylate (110 mg, 0.20 mmol) in DCM (5.0 mL) is added 2,6-lutidine (216 mg, 2.0 mmol, 10.00) and TMSOTf (224 mg, 1.0 mmol) dropwise at RT under N₂ atmosphere. The reaction is stirred for 1 hr then concentrated in vacuo to afford the title compound (400 mg) as a yellow liquid. ES/MS m/z 446.1 [M+H]⁺.

The following compounds are prepared essentially as described for 5-[(1R)-1-(2-Fluorophenyl)ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile using the appropriate reagents, adjusting the reaction times to determine completion of the reactions. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, divalent triflic salt form for each example was not identified. The material was taken on to the next step as isolated.

TABLE 55 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 924 5-[1-(3-Ethyltriazol-4-yl)ethoxy]- 7-[5-methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

447.2 925 5-[1-(2-Isothiazol-3- ylphenyl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

511.2 926¹ 5-[1-(5-Chloro-3- pyridyl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

463.1 927 5-[(1R)-1-(2,4- Difluorophenyl)ethoxy]-7-[5- methyl-1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

464.1 928 5-[1-(2-Isoxazol-3- ylphenyl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

495.2 929 5-[1-(5-Methoxy-3- pyridyl)ethoxy]-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

459.2 930 5-[(1R)-1-(2,6- Difluorophenyl)ethoxy]-7-[5- methyl-1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

464.3 931 5-(1-Isothiazol-4-ylethoxy)-7-[5- methyl-1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

435.1 932 5-(1-Isothiazol-5-ylethoxy)-7-[5- methyl-1-(4-piperidyl)triazol-4- yl]imidazo[1,2-a]pyridine-3- carbonitrile

435.2 933 7-[1-(Azepan-4-yl)-5-methyl- triazol-4-yl]-5-[(1R)-1-(4- fluorophenyl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

461.2 ¹TEA in DCM is used as the solvent. The reaction is quenched by addition of MeOH (5 mL).

Preparation 934 4-Methoxy-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl

A stirred RT mixture of tert-butyl (3R)-3-(4-(3-cyano-4-methoxypyrazolo[1,5-a]310yridine-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)pyrrolidine-1-carboxylate (480 mg, 1.13 mmol) in DCM (5 mL) is treated with 4 M HCl in 1,4-dioxane (5 mL) and stirred for 2 hrs at RT to give white precipitated solids. The precipitated solids are collected by filtration and washed with EtOAc (3×20 mL) to give the title compound as a white solid (350 mg, 84.1%). ES/MS m/z 324.1 [M+H]⁺.

The following compounds are prepared essentially as described for 4-methoxy-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl using the appropriate reagents, adjusting the reaction times to determine completion of the reactions, and adjusting the purification system as appropriate. The residue can also be concentrated under reduced pressure and the crude product washed with DCM. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 56 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 935¹ 6-(1-[1-[2,2- Dimethylazetidin-3- yl]piperidin-4-yl]-5- methylpyrazol-4-yl)-4- methoxypyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

420.30 936² 6-(1-[1-[2,2- Dimethylazetidin-3- yl]piperidin-4-yl]-5- methylpyrazol-4-yl)-4- methoxypyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

420.35 937¹ 4-Methoxy-6-[5-methyl-1- [(3R)-piperidin-3- yl]pyrazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. FA

337.2  938³ 4-Isopropoxy-6-(5-methyl- 1-(piperidin-4-yl)-1H-1,2,3- triazol-4-yl)pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

366.2  939 4-Methoxy-6-[1-(piperidin- 4-yl)pyrazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

323.1  940 4-Methoxy-6-[3-methyl-1- (piperidin-4-yl)pyrazol-4- yl]pyrazolo[1,5-a]pyridine- 3-carbonitrile. HCl

337.2  941 6-[5-Methyl-1-(piperidin-4- yl)pyrazol-4-yl]-4-[(1R)-1- (1-methylpyrazol-3- yl)ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile. HCl

431.2  942⁴ 7-[5-Methyl-1-(4- piperidyl)triazol-4-yl]-5-[3- methyl-1-(2- pyridyl)butoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

471.2  943⁵ 5-[(1R)-1-(5-Fluoro-2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)pyrazol-4- yl]imidazo[1,2- c]pyrimidine-3-carbonitrile

447.2  ¹Reverse Combi-flash chromatography with the following conditions: Column, Xbridge Shield RP18 OBD, 19 * 150 mm, 5 μm, 5-25% ACN in H₂O (10 mmol/L, NH₄HCO₃). ²Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD, 19 * 150 mm, 5 μm, 2-14% ACN in H₂O (10 mmol/L NH₄HCO₃). ³Reverse Combi-flash chromatography with the following conditions: Column, C18, 20-30% ACN in H₂O (0.1% HCl). ⁴Residue is triturated in MTBE, filtered, and the filter cake is dried. ⁵Residue is taken up into 3:1 CHCl₃:IPA, washed with NaHCO₃ solution, H₂O and brine. Dried over Na₂SO₄, filtered, and concentrated in vacuo.

Preparation 944 4-Methoxy-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

A solution of tert-butyl (3R)-3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)pyrrolidine-1-carboxylate (950.00 mg, 2.25 mmol) in TFA (5 mL) and DCM (5 mL) is stirred for 1 hr at RT and concentrated under reduced pressure. The residue is purified directly by reverse Combi-flash chromatography with the following conditions: Column, C18 gel; eluting with a gradient of 25% to 30% ACN in H₂O (0.1% TFA). The purified residue is concentrated under vacuum, the pH is adjusted to 10 with sat. Na₂CO₃ (aq.) and extracted with EtOAc (3×100 mL). The combined organic extracts are washed with brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure to give the title compound as a white solid (490 mg, 67.6%). The product (50 mg) is repurified by reverse Combi-flash chromatography with the following conditions: Column, C18 gel; eluting with a gradient of 60% to 70% ACN in H₂O (0.1% NH₄HCO₃). The solution is concentrated under vacuum to give the title compound as a white solid (36.2 mg, 72.4%). ES/MS m/z 323.05 [M+H]⁺.

The following compounds are prepared essentially as described for 4-methoxy-6-[5-methyl-1-[(3R)-pyrrolidin-3-yl]pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile adjusting the reaction time to determine completion of the reaction. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 57 Prep ES/MS m/z No. Chemical Name Structure [M + H]⁺ 945 4-Methoxy-6-[5-methyl- methyl-1-[(3S)- pyrrolidin-3-yl]pyrazol- 4-yl]pyrazolo[1,5- a]pyridine-3- carbonitrile

323.2 946 5-[2-Methoxy-1-(2- pyridyl)ethoxy]-7-[5- methyl-1-(4- piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile TFA, Isomer 1

458.9 947 5-(3,4-Dihydro-2H- pyrano[3,2-b]pyridin-4- yloxy)-7-[5-methyl-1- (4-piperidyl)triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile TFA

457.2

Preparation 948 tert-Butyl 3-[4-[4-[3-cyano-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]-1-piperidyl]-2,2-dimethyl-azetidine-1-carboxylate

To 6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridine-3-carbonitrile TFA (250 mg, 0.59 mmol) and tert-butyl 2,2-dimethyl-3-oxoazetidine-1-carboxylate (234 mg, 1.17 mmol) in MeOH (5.0 mL) is added AcOH (71 mg, 1.17 mmol) at RT under N₂. The reaction mixture is stirred for 1 hr at 50° C. then NaBH₃CN (111 mg, 1.76 mmol) is added and stirred overnight at 50° C. The suspension is filtered, the filter cake is washed with EtOAc (3×100 mL), organic layers combined and concentrated in vacuo. The residue is purified by Prep-TLC PE:EtOAc (1:1) to afford the title compound as a yellow solid (90 mg, 26%). ES/MS m/z 610.3 [M+H]⁺.

The following compounds are prepared essentially as described for tert-butyl 3-[4-[4-[3-cyano-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]-1-piperidyl]-2,2-dimethyl-azetidine-1-carboxylate adjusting the reaction time to determine completion of the reaction.

TABLE 58 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 949¹ tert-Butyl 2-[3-[4-[3-cyano- 5-[(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridin-7-yl]-5-methyl- pyrazol-1-yl]azetidin-1-yl]- 7-azabicyclo[2.2.1]heptane- 7-carboxylate

595.1 950² tert-Butyl 2-[3-[4-(3-cyano- 4-methoxy-pyrazolo[1,5- a]pyridin-6-yl)-5-methyl- pyrazol-1-yl]azetidin-1-yl]- 7-azabicyclo[2.2.1]heptane- 7-carboxylate

504.2 ¹Purified by Prep-TLC, PE/EtOAc (1:1) ²Purified by silica gel column chromatography, eluting with PE:EtOAc (1:1).

Preparation 951 6-[1-[1-(2,2-Dimethylazetidin-3-yl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridine-3-carbonitrile TFA

To tert-butyl 3-[4-[4-(3-cyano-4-[[(1R)-1-(pyridin-2-yl)ethyl]amino]pyrazolo[1,5-a]pyridin-6-yl)-5-methylpyrazol-1-yl]piperidin-1-yl]-2,2-dimethylazetidine-1-carboxylate (90 mg, 0.15 mmol) in DCM (3.0 mL) is added TFA (1.0 mL) at RT under N₂. The reaction is stirred 1 hr at RT then concentrated in vacuo to afford the title compound as a yellow solid (110 mg). ES/MS m/z 510.3 [M+H]⁺.

The following compounds are prepared essentially as described for 6-[1-[1-(2,2-dimethylazetidin-3-yl)-4-piperidyl]-5-methyl-pyrazol-4-yl]-4-[[(1R)-1-(2-pyridyl)ethyl]amino]pyrazolo[1,5-a]pyridine-3-carbonitrile TFA adjusting the reaction time to determine completion of the reaction. HCl in 1,4-dioxane can be used instead of TFA. For compounds where the amine salt was isolated, the formation of the mono-, di-, or trivalent salt is dependent on the pKa of the amine and the acid used to form the salt. The exact mono-, di-, or trivalent salt form for each example was not identified.

TABLE 59 ES/MS Prep m/z No. Chemical Name Structure [M + H]⁺ 952 7-[1-[1-(7- Azabicyclo[2.2.1]heptan-2- yl)azetidine-3-yl]-5-methyl- pyrazol-4-yl]-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile HCl

495.1 953 6-[1-[1-(7- Azabicyclo[2.2.1]heptan-2- yl)azetidin-3-yl]-5-methyl- pyrazol-4-yl]-4-methoxy- pyrazolo[1,5-a]pyridine-3- carbonitrile TFA

404.2

Preparation 954 6-[1-(1-Cyano-4-piperidyl)-5-methyl-pyrazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-[1-(5-Fluoro-2-pyridyl)-2-hydroxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile (2.3 g, HCl salt), DIEA (6.44 g, 49.84 mmol) and BrCN (0.63 g, 5.98 mmol) in DCM (50 mL) is stirred for 1 hr at RT under N₂. The reaction is quenched with H₂O (400 mL) then extracted with EtOAc (3×100 mL). The combined organic layers are washed with brine (200 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with 40% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (1.46 g, 60.2%) as a white solid. ES/MS m/z 487.3 [M+H]⁺.

Preparation 955 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile

To a stirred solution of 2-[3-Chloro-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol. HCl (165 mg, crude) and DIEA (452 mg, 3.50 mmol) in DCM (1 mL) is added BrCN (44 mg, 0.42 mmol) at RT under N₂. After stirring 1 hr at RT, the reaction is concentrated in vacuo. The residue is purified by Prep-TLC (PE/EtOAc 1:5 to afford the title compound as a light-yellow solid (110 mg, 63.31%). ES/MS m/z 497.2 [M+H]⁺.

Preparation 956 4-[4-[3-Chloro-5-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]imidazo[1,2-a]pyridine-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile

A mixture of 2-[3-chloro-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridin-5-yl]oxy-2-(5-fluoro-2-pyridyl)ethanol HCl (300 mg, 0.64 mmol), DIEA (0.82 g, 6.36 mmol) and BrCN (74 mg, 0.70 mmol) in DCM (12.00 mL) is stirred at RT for 1 hr under N₂. The reaction is concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 70% ACN in H₂O (0.1% NH₄HCO₃; UV 254 nm; to afford the title compound as an off-white solid (120 mg, 37.99%). ES/MS m/z 497.2 [M+H]⁺.

Preparation 957 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile

To 7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile HCl (300.00 mg, 0.60 mmol) in DCM (5.00 mL) is added DIEA (0.774 g, 5.99 mmol) and BrCN (76.19 mg, 0.72 mmol) in portions at RT under N₂. The resulting mixture is stirred for 1 hr at RT then concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; mobile phase; eluting with a gradient of 50% to 60% ACN in water (0.1% NH₄HCO₃); UV 254 nm; to afford the title compound as a grey solid (200 mg, 63.49%). ES/MS m/z 526.2 [M+H]⁺.

Preparation 958 4-(4-[3-Cyano-4-[2,2,2-trifluoro-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carbonitrile

A stirred solution of 6-[5-methyl-1-(piperidin-4-yl)pyrazol-4-yl]-4-[2,2,2-trifluoro-1-(oxan-4-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl (250.00 mg, crude) and DIEA (661.41 mg, 5.12 mmol) in DCM (5.00 mL) is treated with BrCN (65.05 mg, 0.61 mmol) in portions at RT under N₂ and the mixture is stirred for 1 hr at RT under N₂. The solution is diluted with DCM (80 mL), washed with sat. NaHCO₃ (2×20 mL) and brine (15 mL), and the H₂O phase is quenched by sodium hypochlorite soln (100 mL). The combined organic layers are dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 50% to 55% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (100 mg, 38.05%). ES/MS m/z 514.3 [M+H]⁺.

Preparation 959 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)319yridine319-1-yl]-2,2-dimethylpyrrolidine-1-carbonitrile

A stirred solution of 6-[1-[1-(5,5-dimethylpyrrolidin-3-yl)319yridine319-3-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (250.0 mg, 0.62 mmol) in DCM (5.0 mL) at RT under N₂ is treated with DIEA (796.8 mg, 6.17 mmol) and BrCN (58.8 mg, 0.56 mmol), and the mixture is stirred for 1 hr at RT under N₂. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 70% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (100 mg, 37.4%). ES/MS m/z 431.2 [M+H]⁺.

Preparation 960 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile

A mixture of 7-[5-methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile.TFA (140.00 mg, 0.28 mmol) in DCM (15.00 mL) at RT under N₂ is treated with DIEA (364.43 mg, 2.82 mmol) and BrCN (35.84 mg, 0.34 mmol). The mixture is stirred for 2 hr at RT under N₂ and is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 0 to 100% ACN in H₂O (0.1% FA) to give the title compound as a light-yellow solid. ES+H m/z 522.2 [M+H]⁺.

Preparation 961 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile

A mixture of 5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.TFA (150.00 mg), DIEA (542.45 mg, 4.20 mmol) and BrCN (48.90 mg, 0.462 mmol) in DCM (6.00 mL) is stirred for 2 hr at RT under N₂ and concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography eluting with 50% to 55% ACN in H₂O (0.1% NH₄HCO₃), to give the title compound (110 mg, 69.68%) as an off-white solid. ES/MS m/z 502.2 [M+H]⁺

Preparation 962 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridine-3-carbonitrile

A mixture of 5-[1-(5-fluoro-2-pyridyl)propoxy]-7-[5-methyl-1-(4-piperidyl)triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl (200 mg), DIEA (561 mg, 4.34 mmol) and BrCN (55 mg, 0.52 mmol) in DCM (6.00 mL) is stirred for 2 hr at RT under N₂. The resulting mixture is concentrated under reduced pressure. The residue is purified by reversed Combi-flash chromatography eluting with 45% to 50% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (150 mg, 71.14%) as an off-white solid. ES/MS m/z 486.4 [M+H]⁺.

Preparation 963 6-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile

A mixture of 4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile HCl, DIEA (406.84 mg, 3.15 mmol) and BrCN (36.68 mg, 0.35 mmol) in DCM (4.00 mL) is stirred for 2 hr at RT under N₂. The mixture is concentrated under reduced pressure and then is purified by reversed Combi-flash chromatography eluting with 50% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound (140 mg, 88.63%) as an off-white solid. ES/MS m/z 502.2 [M+H]⁺.

The following compounds are prepared essentially as described for 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 60 Prep ES/MS m/z No. Chemical Name Structure [M + H]+ 964 4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)-2,2- dimethylpyrrolidine-1- carbonitrile

376.0 965¹ 6-(1-(1-Cyanopiperidin-4- yl)-5-methyl-1H-1,2,3- triazol-4-yl)-4-((6,6- difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-7- yl)oxy)pyrazolo[1,5- a]pyridine-3-carbonitrile

502.3 966 6-[1-(1-cyano-4-piperidyl)- 5-methyl-triazol-4-yl]-4-[2- methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

552.2 967² 7-[1-(1-Cyano-4-piperidyl)- 5-methyl-triazol-4-yl]-5-[1- (5-fluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

488.1 968⁵ 4-(4-bromo-5-methyl- triazol-1-yl)piperidine-1- carbonitrile

(⁷⁹Br/⁸¹Br) 270.0/272.0 ¹Purified by Prep-TLC (PE:EtOAc 2:1). ²Purified by Xbridge C18 Column, 50*250 mm, 10 μm; eluting with 10% to 40% ACN in H₂O (10 mmol/L NH₄HCO₃), B; flow rate: 25 mL/min; 254/220 nm. ³Purified by Prep-TLC (PE:EtOAc 1:2). ⁴Purified by Prep-TLC (PE:EtOAc 1:1). ⁵Purified by reverse phase chromatography eluting with 38% to 48% ACN in H₂O (0.1% NH₄HCO₃), 254 nm.

Example 1 2-[1-[3-Cyano-6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxyethyl]benzamide

2-[1-[3-cyano-6-[5-methyl-1-(4-piperidyl)triazol-4-yl]pyrazolo[1,5-a]pyridin-4-yl]oxyethyl]benzamide (63 mg, 0.13 mmol) and DIEA (52 mg, 0.40 mmol) in DCM (0.9 mL) is added a solution of BrCN (14 mg, 0.13 mmol) in DCM (0.1 mL). The mixture is stirred for 10 m then concentrated in vacuo. The residue is purified by reverse phase chromatography to afford the title compound (33 mg) LCMS m/z: [M+H]: 496.2; Rt=0.84 min

The following compounds are prepared essentially as described for 2-[1-[3-Cyano-6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]pyrazolo[1,5-a]pyridine-4-yl]oxyethyl]benzamide using the appropriate reagents and adjusting the reaction times to determine completion of the reactions.

TABLE 61 Example ES/MS m/z No. Chemical Name Structure [M + H]⁺ 2¹ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methylpyridazin-3- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

469.2 3² 4-[1-(5-Chloropyridazin- 3-yl)ethoxy]-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile

489.10 4³ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methylpyridazin-3- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

469.20 5⁴ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-3- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

468.20 6⁴ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (difluoromethyl)-3- pyridyl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

504.2 7² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(1- methylpyrrolo[2,3- c]pyridin-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

507.2 8⁵ 2-[1-[3-cyano-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridin-4-yl]oxyethyl]- N,N-dimethyl-benzamide

524.2 9² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(2- ethyltriazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

472.2 10⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methyl-3- pyridyl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

468.2 11⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[5- (difluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

504.2 12³ 5-[1-(5-Chloropyridazin- 3-yl)ethoxy]-7-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3-carbonitrile

489.2 13⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[2- morpholino-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

607.20 14⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methyl-1,3,4-thiadiazol- 2-yl)ethoxy] pyrazolo[1,5-a]pyridine- 3-carbonitrile

475.2 15⁴ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(1- isopropyltriazol-4- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

486.2 16⁶ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(6- methylpyrazin-2- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

469.1 17  7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(6- methylpyrazin-2- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

469.20 18² 6-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2- hydroxy-1-(4- isoquinolyl)ethoxy] pyrazolo[1,5-a] pyridine-3- carbonitrile

520.2 19² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-[1-(2- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

530.1 20² 5-[1-(1,3-Benzothiazol- 7-yl)ethoxy]-7-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3-carbonitrile

532.2 21² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(7- fluoro-4- isoquinolyl)ethoxy] pyrazolo[1,5-a] pyridine-3- carbonitrile

522.2 22⁵ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2-fluoro- 1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

490.8 23⁷ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4- [cyclopropyl-(5-fluoro-2- pyridyl)methoxy] pyrazolo[1,5-a] pyridine-3- carbonitrile

497.8 24² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(4- isoquinolyl)ethoxy] pyrazolo[1,5-a] pyridine-3- carbonitrile

504.20 25⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(2- methyltriazol-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

458.2 26² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[(1- fluorocyclopropyl)-(5- fluoro-2- pyridyl)methoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

515.8 27⁷ 4-[1-(1,2-Benzothiazol- 7-yl)ethoxy]-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile

510.2 28⁷ 5-[1-(1,2-Benzothiazol- 7-yl)ethoxy]-7-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3-carbonitrile

510.1 29⁸ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3- methylsulfonylphenyl) ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

531.1 30⁸ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(2- isothiazol-3- ylphenyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

534.2 [M − H]⁺ 31⁵ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,3- difluorocyclobutyl)ethoxy] imidazo[1,2- a]pyridine-3-carbonitrile

467.2 32⁵ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-1,3,4-thiadiazol- 2-yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile

475.1 33⁷ 6-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(4- methylisothiazol-5- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile

474.2 34² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[2-(1- hydroxy-1-methyl- ethyl)phenyl]ethoxy] pyrazolo[1,5-a] pyridine-3-carbonitrile

510.8 35⁴ 4-[4-[3-Chloro-4-[2- cyano-1-(5-fluoro-2- pyridyl)-2-methyl- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

535.7 36⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[2-(2- methoxyethylamino)-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

595.3 37⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[2-(3- hydroxyazetidin-1-yl)-5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

593.3 38⁶ 4-[4-[3-Bromo-4-[(2R)- 1-(5-fluoro-2-pyridyl)- 2,3-dihydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

(⁷⁹Br/⁸¹Br) 570.6/ 572.6 ¹Purification: Prep-TLC (PE/EtOAc 1:2) ²Reverse phase flash chromatography eluting with 0% to 100% ACN in H₂O. ³Reverse phase flash chromatography eluting with 0% to 50% ACN in H₂O. ⁴Reverse phase C18 chromatography eluting with 10% to 100% ACN in H₂O. ⁵Reverse phase flash chromatography eluting ACN in H₂O. ⁶Reverse phase C18 chromatography eluting with 10% to 100% ACN in H₂O followed by Prep HPLC system eluting with 10% to 100% ACN in H₂O. ⁷Reverse phase C18 chromatography eluting with 0% to 100% ACN in H₂O. ⁸Reverse phase C18 chromatography eluting with ACN in H₂O (0.1% FA).

Example 39 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]-2,2-dimethyl-pyrrolidine-1-carbonitrile, Isomer 1 and Example 40 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]-2,2-dimethyl-pyrrolidine-1-carbonitrile, Isomer 2

4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]-2,2-dimethylpyrrolidine-1-carbonitrile (100 mg) is separated by Chiral-HPLC with the following conditions: Column, CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; eluting with 1:1 hexanes:DCM and 30% iPrOH, 254/210 nm; t_((R)) Isomer 1 is 6.15 min (33.1 mg, 32.9%) as a white solid with 100% ee, t_((R)) Isomer 2 is 9.07 min (35.5 mg, 35.2%) as a white solid with 100% ee. ES/MS m/z 431.20 [M+H]⁺.

Example 41 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 1 and Example 42 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 2

7-[5-Methyl-1-(4-piperidyl)triazol-4-yl]-5-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile.TFA (90.00 mg) is separated by Chiral-HPLC with the following conditions: Column CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 30% MTBE (0.1% diethylamine) and EtOH, 254/210 nm; 20 mL/min; t_((R)) Isomer 1 is 6 min (35.3 mg, 38.83%) with 100% ee, t_((R)) Isomer 2 is 10.4 min (34.6 mg, 37.87%) with 100% ee, ES/MS m/z 522.20 [M+H]⁺.

Example 43 6-[1-(1-Cyano-4-piperidyl)-5-methyl-pyrazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1 and Example 44 6-[1-(1-Cyano-4-piperidyl)-5-methyl-pyrazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

6-[1-(1-Cyano-4-piperidyl)-5-methyl-pyrazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile is separated by prep-chiral-HPLC with the following conditions: Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 50% hexanes (10 mM NH₃ in MeOH) in iPrOH, 254/270 nm, t_((R)) Isomer 1 is 11.90 min (319 mg, 35.4%) with 99% ee, ES/MS m/z 487.2 [M+H]⁺, t_((R)) Isomer 2 is 16.12 min (320 mg, 35.4%) with 96.1% ee, ES/MS m/z 487.2 [M+H]⁺.

Example 45 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 1 and Example 46 4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 2

4-[4-[3-Chloro-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile is separated by prep-chiral-HPLC with the following conditions: Column: ART Cellulose-SB, 2*25 cm, 5 μm; eluting with 20% 5:1 Hex:DCM (0.5% 2M NH₃ in MeOH) in EtOH, 210/244 nm; t_((R)) Isomer 1 is 6.81 min (32 mg, 29.1%) with 100% ee, ES/MS m/z 497.2 [M+H]⁺, t_((R)) Isomer 2 is 8.00 min (31 mg, 28.2%) with 96.7% ee, ES/MS m/z 497.2 [M+H]⁺.

Example 47 4-[4-[3-Chloro-5-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]imidazo[1,2-a]pyridine-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 2

4-[4-[3-chloro-5-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile is separated with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; eluting with 30% EtOH:ACN (2:1) in hexanes (10 mM NH₃ in MeOH); 246/310 nm; t_((R)) Isomer 1 is 14.56 min (39.6 mg, 12.5%) as an off-white solid with 99.5% ee, t_((R)) Isomer 2 is 17.6 min (44.6 mg, 14.1%) as an off-white solid with 95.12% ee. ES/MS m/z 497.2 [M+H]⁺.

Example 48 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 1

7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[2,2,2-trifluoro-1-(5-fluoro-2-pyridyl)ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile is separated with the following condition: Column: NB Lux i-Cellulose-5, 2.12*25 cm, 5 μm; eluting with 30% MTBE (10 mM NH₃ in MeOH) in EtOH; 254/320 nm; t_((R)) Isomer 1 is 11.61 min (52.3 mg, 26.15%) with 100% ee, ES/MS m/z 526.2 [M+H]⁺.

Example 49 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 1 and Example 50 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 2

7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]imidazo[1,2-a]pyridine-3-carbonitrile (110.00 mg) is separated by prep-chiral-HPLC with the following conditions: Column CHIRALPAK ID, 2*25 cm, 5 m; eluting with 30% MTBE (10 mM NH₃-MeOH) and EtOH, 254/320 nm, t_((R)) Isomer 1 is 8.65 min (36.6 mg) with 100% ee, t_((R)) Isomer 2 is 11.51 min (30.9 mg) with 100% ee, ES/MS m/z 502.35 [M+H]⁺.

Example 51 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 1 and Example 52 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 2

7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[1-(5-fluoro-2-pyridyl)propoxy]imidazo[1,2-a]pyridine-3-carbonitrile (120 mg) is separated by prep-chiral-HPLC with the following conditions: Column: (R,R)-WHELK-01-Kromasil, 5*25 cm, 5 um; eluting with 50% hexanes (10 mM NH₃-MeOH) and EtOH, 254/220 nm, t_((R)) Isomer 1 is 7.27 min (52.9 mg) with 100% ee, t_((R)) Isomer 2 is 14.52 min (53.1 mg) with 100% ee, ES/MS m/z 486.20 [M+H]⁺.

Example 53 6-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1 Example 54 6-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

6-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-(5-fluoro-2-pyridyl)-2-methoxy-ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (160 mg) is isolated by prep-chiral-HPLC with the following conditions: Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 30% MTBE (10 mM NH3-MeOH) and EtOH, 250/215 nm, t_((R)) Isomer 1 is 7.06 min (61.5 mg) with 100% ee, t_((R)) Isomer 2 is 9.34 min (70.6 mg) with 100% ee, ES/MS m/z 502.20 [M+H]⁺.

The following compounds are prepared essentially as described for 4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridine-6-yl]-5-methylpyrazol-1-yl)pyridine-1-yl]-2,2-dimethylpyrrolidine-1-carbonitrile, Isomer 1 and Isomer 2, and adjusting the purification system as appropriate.

TABLE 62 ES/MS Ex. m/z tR No. Chemical name Structure [M + H]⁺ min 55¹ 4-(4-[3-Cyano-4-[2,2,2- trifluoro-1-(oxan-4- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile, Isomer 1

513.9 6.36 56¹ 4-(4-[3-Cyano-4-[2,2,2 trifluoro-1-(oxan-4- yl)ethoxy]pyrazolo[1,5 a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile, Isomer 2

513.9 8.04 57² 4-(4-[3-Cyano-4-[(6,6- difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-7- yl)oxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- 1H-1,2,3-triazol-1- yl)piperidine- carbonitrile, Isomer 1

502.0 15.61 58² 4-(4-[3-Cyano-4-[(6,6- difluoro-6,7-dihydro-5H- cyclopenta[b]pyridin-7- yl)oxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- 1H-1,2,3-triazol-1- yl)piperidine- carbonitrile, Isomer 2

502.0 19.2 59³ 4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)-2,2- dimethylpyrrolidine-1- carbonitrile, Isomer 1

376.0 6.3 60³ 4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)-2,2- dimethylpyrrolidine-1- carbonitrile, Isomer 2

376.0 8.6 61⁴ 6-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2- methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 1

552.3 4.47 62⁴ 6-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2- methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 2

552.3 7.66 63⁵ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 1

488.2 6.99 64⁵ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 2

488.3 10.75 65⁶ 2-[1-[3-Cyano-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridin-4- yl]oxyethyl]benzamide, Isomer 1

496.4 3.18⁵ 66⁷ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methylpyridazin-3- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

469.2 1.53 67⁷ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methylpyridazin-3- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

469.2 2.03 68⁸ 4-[1-(5-Chloropyridazin- 3-yl)ethoxy]-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

489.1 1.66 69⁹ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methylpyridazin-3- yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 1

469.2 1.56 70¹⁰ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-3- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

468.2 2.42 71¹⁰ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-3- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

468.3 3.03 72¹¹ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (difluoromethyl)-3- pyridyl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

504.3 1.94 73¹¹ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (difluoromethyl)-3- pyridyl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

504.4 2.47 74¹² 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(1- methylpyrrolo[2,3- c]pyridin-4- yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

507.4 1.42 75¹³ 2-[1-[3-cyano-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridin-4-yl]oxyethyl]- N,N-dimethyl- benzamide, Isomer 2

524.2 4.23 76¹⁴ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-[1-(2- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

530.2 2.22 77^(14,15) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-[1-(2- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

530.2 2.85 78^(12,16) 5-[1-(1,3-Benzothiazol- 7-yl)ethoxy]-7-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 1

510.2 1.94 79^(17,18) 4-[1-(1,2-benzothiazol-7- yl)ethoxy]-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 1

510.9 1.87 80^(17,18) 4-[1-(1,2-benzothiazol-7- yl)ethoxy]-6-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

510.8 2.85 81¹⁹ 6-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-[1-(3- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3-carbonitrile, Isomer 2

531.0 1.57 82^(20,21) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,3- difluorocyclobutyl) ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 1

467.2 0.75 83^(20,21) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,3- difluorocyclobutyl) ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 2

467.2 0.84 84^(22,23) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-1,3,4-thiadiazol- 2-yl)ethoxy]imidazo[1,2- a]pyridine-3-carbonitrile, Isomer 2

475.2 2.65 ¹Column CHIRAL ART Amylose-SA, 2*25 cm, 5 μm, eluting with hexanes:DCM (5:1) (0.1% DEA) in 50% EtOH, flow rate 20 mL/min, 220/254 nm. ²Column CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 50% EtOH in MTBE:hexanes (1:1, 0.1% DEA additive) in 22 min, 210/250 nm. ³Column CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm, 40% EtOH in hexanes (10 mM NH₃?MeOH), 25 mL/min, 250/210 nm. ⁴Column CHIRAL ART Cellulose-SC, 2*25 cm, 5 μm; eluting with 40% EtOH in MTBE (10 mM NH₃-MeOH); 20 mL/min; 250/215 nm. ⁵Column CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 50% EtOH in MTBE (10 mM NH₃?MeOH); flow rate: 20 mL/min; 254/210. ⁶Column: (S,S) Whelk-01, 21 x 250 mm; eluting with an 65% CO₂ in MeOH (0.5% DMEA); flow rate 80 mL/min; UV at 225 nm. ⁷Column: CHIRALPAK AD-H, 21*150 mm; eluting with a 65% CO₂ in EtOH (0.5% DMEA); flow rate 80 mL/min; UV at 245 nm. ⁸Column: CHIRALPAK AD-H, 21*150 mm; eluting with a 60% CO₂ in MeOH (0.5% DMEA); flow rate 80 mL/min; UV at 245 nm. ⁹Column: CHIRALPAK AD-H, 21*250 mm; eluting with a 60% CO₂ in MeOH (0.5% DMEA); flow rate 70 mL/min; UV at 225 nm. ¹⁰Column: CHIRALPAK AD-H, 20*150 mm; eluting with a 70% CO₂ in EtOH (0.5% DMEA); flow rate 80 mL/min; UV at 254 nm. ¹¹Column: CHIRALPAK AD-H, 21*250 mm; eluting with a 70% CO₂ in EtOH (0.5% DMEA); flow rate 70 mL/min; UV at 225 nm. ¹²Column: Chiralpak AD-H, 21*150 mm; eluting with an 70% CO₂ in iPrOH (0.5% DMEA); flow rate 80 mL/min; 310 nm. ¹³Column CHIRALPAK AS-H, 21*150 cm, eluting with 85% CO₂ in EtOH (0.5% DMEA additive), flow rate 70 mL/min, 242 nm. ¹⁴Column: Lux Sum Cellulose-4, 2.12*250 mm, eluting with 60% CO₂ in EtOH (0.5% DMEA). ¹⁵Reported t_((R))'s are obtained using the following analytical conditions: SFC, Lux 5 μm Cellulose-4, 4.6*100 mm, 40% EtOH (0.5% DMEA)/CO₂. ¹⁶Reported t_((R))'s are obtained using the following analytical conditions: SFC, Chiralpak AD-H, 4.6 x 150 mm, 30% iPrOH (0.5% DMEA)/CO₂, 5 mL/min, 225 nm. ¹⁷Column: CHIRALPAK AD-H, 21*150 mm; eluting with a 60% CO₂ in MeOH; 225 nm. ¹⁸Reported t_((R))'s are obtained using the following analytical conditions: SFC, Chiralpak AD-H, 4.6 x 150 mm, 40% MeOH/CO₂, 5 mL/min, 225 nm. ¹⁹Column CHIRALPAK AS-H, 21*150 cm, eluting with 75% CO₂ in MeOH, flow rate 80 mL/min, 225 nm. ²⁰Column: CHIRALPAK AD-H, 21*250 mm; eluting with a 75% CO₂ in EtOH (0.5% DMEA); flow rate 70 mL/min; UV at 255 nm. ²¹Reported t_((R))'s are obtained using the following analytical conditions: SFC, Chiralpak AD-H, 4.6 x 150 mm, 25% EtOH (0.5% DMEA)/CO₂, 5 mL/min, 225 nm. ²²Column: Chiralcel-OD-H, 21*250 mm; eluting with a 60% CO₂ in MeOH (0.5% DMEA); flow rate 80 mL/min; UV at 225 nm. ²³Reported t_((R))'s are obtained using the following analytical conditions: Column: Chiralcel-OD-H, 4.6*150 mm; eluting with a 40% MeOH (0.5% DMEA)/CO₂; flow rate 5 mL/min; UV at 225 nm.

Example 85 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1 and Example 86 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2

To 6-[5-methyl-1-(4-piperidyl)triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (200.00 mg, 0.40 mmol) in DCM (5 mL) is added DIEA (520.62 mg, 4.03 mmol) and BrCN (51.20 mg, 0.48 mmol) in portions at RT under N₂. The reaction is stirred 2 hr at RT then concentrated in vacuo. The residue is purified by reverse phase chromatography with the following conditions: Column, C18; mobile phase, eluting with 50% to 60% ACN in H₂O (0.1% NH₄HCO₃) to afford the titled compound as a white solid (170 mg, 80.92%). ES/MS m/z 522.1 [M+H]⁺.

6-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile is subjected to prep-chiral-HPLC: Column, CHIRAL ART Amylose-SA, 2*25 cm, 5 m; eluting with 10% EtOH in Hex:DCM (5:1) (0.5% 2M NH₃-MeOH) to afford 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy] pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 1, t_((R)) is 16.5 min (30.5 mg, 17.9%) with 99.7% ee, ES/MS m/z 522.15 [M+H]⁺ and 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy] pyrazolo[1,5-a]pyridine-3-carbonitrile, Isomer 2, t_((R)) Isomer 2 is 22.5 min (42.1 mg, 24.8%) with 98.0% ee, ES/MS m/z 522.10 [M+H]⁺.

The following compounds are prepared essentially as described for 6-[1-(1-cyano-4-piperidyl)-5-methyl-triazol-4-yl]-4-[1-[5-(trifluoromethyl)-3-pyridyl]ethoxy]pyrazolo [1,5-a]pyridine-3-carbonitrile, Isomer 1, and Isomer 2, and adjusting the purification system as appropriate. Retention times reported in Table 57 are for the separated enantiomers.

TABLE 63 ES/MS Ex. m/z t_((R)) No. Chemical name Structure [M + H]⁺ min  87^(1,2) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[(5- fluoro-2-pyridyl)-[1- (trifluoromethyl)cyclo- propyl]methoxy] pyrazolo[1,5-a] pyridine-3- carbonitrile, Isomer 2

566.4 12.8  88^(3,4) 6-[1-(7-Cyano-7- azaspiro[3.5]nonan-2- yl)-5-methyl-pyrazol- 4-yl]-4-[1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 1

527.2 4.6  89^(5,6) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methylthiazol-2- yl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 1

474.2 14.6  90^(5,6) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- methylthiazol-2- yl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 2

474.2 17.6  91^(7,8) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 1

488.2 5.1  92^(7,8) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

488.2 8.9  93^(9,10) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(1- isopropyltriazol-4- yl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer I

486.4 1.2  94^(11,12) 6-[1-[1-(1-Cyano-2,2- dimethyl-azetidin-3- yl)-4-piperidyl]-5- methyl-pyrazol-4-yl]- 4-[[(1R)-1-(2- pyridyl)ethyl]amino] pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 1

535.4 10.1  95^(11,12) 6-[1-[1-(1-Cyano-2,2- dimethyl-azetidin-3- yl)-4-piperidyl]-5- methyl-pyrazol-4-yl]- 4-[[(1R)-1-(2- pyridyl)ethyl] amino]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

535.4 12.8  96^(13,14) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[3,3,3- trifluoro-1-(5-fluoro- 2-pyridyl) propoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

540.3 8.3  97^(15,16) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3- ethyltriazol-4- yl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

472.2 13.6  98^(17,18) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- fluoro-2-pyridyl)-3- hydroxy- propoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 2

502.2 12.2  99^(11,19) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[6- (trifluoromethyl) pyrazin-2- yl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

523.3 11.4 100^(20,21) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2- hydroxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

538.1 7.0 101^(13,22) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,5- difluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

506.1 7.3 102^(13,22) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,5- difluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

506.1 8.8 103^(23,24) 7-[1-(7-Cyano-7- azaspiro[3.5]nonan-2- yl)-5-methyl-triazol-4- yl]-5-[1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

528.2 8.0 104^(23,24) 7-[1-(7-Cyano-7- azaspiro[3.5]nonan-2- yl)-5-methyl-triazol-4- yl]-5-[1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

528.3 13.0 105^(15,82) 7-[1-(1-cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

487.2 12.7 106^(26,24) 5-[1-(5-Chloro-2- pyridyl)-2-hydroxy- ethoxy]-7-[1-(1- cyano-4-piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

504.3 9.0 107^(17,27) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2- hydroxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy] pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 2

538.3 10.1 108^(28,29) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-3- hydroxy- propoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

502.2 10.2 109^(28,29) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-3- hydroxy- propoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

502.2 12.8 110^(32,33) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[3- methyl-1-(2- pyridyl)butoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

496.2 30.1 111^(34,35) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2- cyclopropyl-1-(2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

494.2 9.8 112^(34,35) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2- cyclopropyl-1-(2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

494.2 11.8 113^(36,37) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(3,4- dihydro-2H- pyrano[3,2-b]pyridin- 4-yloxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

481.2 1.5 114^(38,39) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(6,6- dimethyl-5,7- dihydrocyclopenta[b] pyridin-7- yl)oxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

494.3 10.3 115^(38,39) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(6,6- dimethyl-5,7- dihydrocyclopenta[b] pyridin-7- yl)oxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

494.3 12.1 116^(40,41) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,5- difluoro-2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

489.8 18.6 117^(40,41) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(3,5- difluoro-2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

489.8 21.9 118^(40,42) 6-[1-(1-Cyano-3,3- difluoro-4-piperidyl)- 5-methyl-pyrazol-4- yl]-4-methoxy- pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 1

398.1 4.2 119^(40,42) 6-[1-(1-Cyano-3,3- difluoro-4-piperidyl)- 5-methyl-pyrazol-4- yl]-4-methoxy- pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

398.1 7.3 120^(43,44) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2- pyridyl-[1- (trifluoromethyl)cyclo- propyl]methoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

548.2 5.6 121^(45,46) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methyl-2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

468.1 5.5 122^(47,48) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(1- isothiazol-4- ylethoxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

460.2 6.6 123^(47,48) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(1- isothiazol-4- ylethoxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

460.2 8.5 124^(49,50) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(1- isothiazol-3- ylethoxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

460.1 12.5 125^(49,50) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(1- isothiazol-3- ylethoxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

460.0 18.3 126^(17,51) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[5- (trifluoromethyl)-3- pyridyl]ethoxy] pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 1

522.2 16.5 127^(17,51) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-[5- (trifluoromethyl)-3- pyridyl]ethoxy] pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 2

522.1 22.5 128^(52,53) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-(1- isothiazol-5- ylethoxy)imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

460.1 7.1 129^(40,56) 6-[1-(1-Cyano-3,3- difluoro-4-piperidyl)- 5-methyl-pyrazol-4- yl]-4-methoxy- pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

398.1 7.3 130^(54,55) 7-[1-(1-Cyanoazepan- 4-yl)-5-methyl-triazol- 4-yl]-5-[1-(5-fluoro-2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

486.3 10 131^(54,55) 7-[1-(1-Cyanoazepan- 4-yl)-5-methyl-triazol- 4-yl]-5-[1-(5-fluoro-2- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

486.3 26 132^(49,58) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methoxy-3- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

484.1 4.7 133^(49,58) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methoxy-3- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

484.2 7.9 134^(59,60) 5-[1-(6-Chloro-3- pyridyl)ethoxy]-7-[1- (1-cyano-4-piperidyl)- 5-methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

(³⁵Cl/³⁷Cl) 488.4/ 490.4 6.8 135^(59,60) 5-[1-(6-Chloro-3- pyridyl)ethoxy]-7-[1- (1-cyano-4-piperidyl)- 5-methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

(³⁵Cl/³⁷Cl) 488.4/ 490.4 10.1 136^(61,62) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (trifluoromethyl) isoxazol-3- yl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

512.1 16.4 137^(61,62) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (trifluoromethyl) isoxazol-3- yl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

512.1 19.4 138^(63,64) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2,2- difluoro-1-(5-fluoro- 2-pyridyl) ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

508.2 18.4 139^(63,64) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2,2- difluoro-1-(5-fluoro- 2-pyridyl) ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

508.2 21.6 140^(65,66) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(5- fluoro-2-pyridyl)-[1- (trifluoromethyl) cyclopropyl]methoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

 566.15 15.7 141^(78,67) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[2- methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

 552.10 15.1 142^(79,68) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(2- isoxazol-3- ylphenyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 2

 520.20 14.6 143^(80,69) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-3- pyridyl)ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

472.2 6.0 144^(17,70) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[1-(5- fluoro-2-pyridyl)-2- methoxy- ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

 502.20 9.3 145^(81,71) 5-[1-(5-Chloro-3- pyridyl)ethoxy]-7-[1- (1-cyano-4-piperidyl)- 5-methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

488.1 6.5 146^(72,73) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- methylthiazol-2- yl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

 474.15 7.7 147^(74,75) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-4-[2- methoxy-1-[5- (trifluoromethyl)-3- pyridyl]ethoxy] pyrazolo [1,5-a]pyridine-3- carbonitrile, Isomer 1

552.3 4.5 148^(76,77) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(6,6- difluoro-5,7- dihydrocyclopenta[b] pyridin-7- yl)oxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

502.3 19.5 149^(76,77) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(6,6- difluoro-5,7- dihydrocyclopenta[b] pyridin-7- yl)oxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

502.3 26.5 150^(15,84) 4-[4-[3-Fluoro-4-[1- (5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

481.2 6.35 151^(85,86) 4-[4-[3-Chloro-4-[2- hydroxy-1-(2- pyridyl)ethoxy] pyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

478.9 6.18 152^(45,87,97) Cis-4-[3-[4-[3-Chloro- 4-[1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]cyclobutyl] piperazine-1- carbonitrile isomer 2

552.2 15.7 153^(9,91) 4-[4-[3-Fluoro-4-[2- (5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

481.2 0.85 154^(9,93) 4-[4-[3-Chloro-4-[2- (5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

497.4 1.40 155^(9,93) 4-[4-[3-Chloro-4-[2- (5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 2

497.4 2.78 156^(9,90) 4-[4-[3-Chloro-4-[2- (5-fluoro-2-pyridyl)- 2-hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

511.2 2.38 157¹⁰³ 4-[4-[3-Fluoro-4-[2- (5-fluoro-2-pyridyl)- 2-hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile, Isomer 1

495.2 3.79 158^(88,89) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-(5- fluoro-2-pyridyl)-2- (trifluoromethoxy) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

556.3 6.51 159^(94,95) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- fluoro-6-(2- methoxyethoxy)-2- pyridyl]ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

546.2 8.44 160^(9,96) 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[1-[5- (trifluoromethoxy)-3- pyridyl]ethoxy] imidazo [1,2-a]pyridine-3- carbonitrile, Isomer 1

538.2 9.21 161^(99,100) (3RS,4RS)-4-[4-[3- chloro-4-[1-(5-fluoro- 2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carbonitrile, Isomer 2A

511.1 9.5 162^(99,100) (3RS,4RS)-4-[4-[3- chloro-4-[1-(5-fluoro- 2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carbonitrile, Isomer 2B

511.1 29.5 163^(101,102) (3RS,4SR)-4-[4-[3- chloro-4-[1-(5-fluoro- 2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carbonitrile, Isomer 2A

511.1 12.3 164^(101,102) (3RS,4SR)-4-[4-[3- chloro-4-[1-(5-fluoro- 2-pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1-yl]-3- methyl-piperidine-1- carbonitrile, Isomer 2B

511.1 14.8 165^(104,105) 6-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-4-[1-(3- methylsulfonylphenyl) ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile, Isomer 2

530.2 1.57 ¹Racemate purification: Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm; eluting with 45% to 80% MeOH in H₂O (10 mmol/L NH₄HCO₃). ²Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 30% EtOH:MeOH (1:3) in hexanes (10 mM NH₃ MeOH); flow rate: 20 mL/min; 246/310. ³Racemate purification: Prep-TLC (PE/EtOAc 1:2) ⁴Chiral ART Cellulose-SA, 2*25 cm, 5 μm; eluting with 40% MeOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 254/314 nm. ⁵Racemate purification: Reverse phase chromatography: Column, C18; eluting with 45% to 50% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁶Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 30% EtOH:ACN (2:1) in hexanes (10 mM NH₃ MeOH); flow rate: 20 mL/min; 246/310. ⁷Racemate purification: Reverse phase chromatography: Column, C18; eluting with 36% to 42% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁸Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 40% EtOH:ACN (2:1) in hexanes (10 mM NH₃ MeOH); flow rate: 20 mL/min; 246/310. ⁹Racemate purification: Reverse phase C18 chromatography eluting with 10% to 100% ACN in H₂O. ¹⁰Column: Chiralpak AD-H, 250 x 21 mm; eluting with an 65% CO₂ in EtOH (w/ 0.5% DMEA); flow rate 70 mL/min; UV at 225 nm. t_((R)) is obtained by SFC using the followinganalytical conditions: Chiralpak AD-H, 4.6 x 150 mm; 35% EtOH (0.5% DMEA)/CO2; 5 mL/min; UV at 225 nm. ¹¹Racemate purification: Prep-TLC (PE/EtOAc = 1:1). ¹²Column: CHIRALPAK IC, 2*25 cm, 5 μm; eluting with 10% EtOH in MTBE (10 mM NH₃ MeOH), flow rate:20 mL/min; 250/330 nm. ¹³Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 50% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ¹⁴Column: Lux Cellulose-4, 2.12*25 cm, 5 μm; eluting with 50% EtOH:ACN (2:1) in Hex (10 mM NH₃ MeOH); flow rate 25 mL/min; 254/318 nm. ¹⁵Racemate purification: Reverse phase chromatography: Column, C18; eluting with 30% to 40% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ¹⁶Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 30% EtOH in Hex: DCM (3:1) (0.5% 2M NH₃ MeOH); flow rate 20 mL/min; 254 nm. ¹⁷Racemate purification: Reverse phase chromatography: Column, C18; eluting with 50% to 60% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ¹⁸Column: CHIRALPAK IA, 2*25 cm, 5 μm; eluting with 50% EtOH in Hex (10 mM NH₃ MeOH), Flow rate: 20 mL/min; 254/210 nm ¹⁹Column: CHIRALPAK IA, 2*25 cm, 5 μm; eluting with 10% EtOH in hexanes:MTBE (1:1) (0.5% 2M NH₃—MeOH). ²⁰Racemate purification: Reverse phase chromatography: Column, C18; eluting with 70% to 80% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ²¹Column:Chiral ART Cellulose-SC, 2*25 cm, 5 μm; eluting with 30% MeOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 254/320 nm. ²²Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 18 mL/min; 254/230. ²³Racemate purification: Reverse phase chromatography: Column, C18; eluting with 50% to 55% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ²⁴Column: CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 50% MeOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min; 254/320. ²⁵Column: CHIRALPAK IA, 2*25 cm, 20 μm; eluting with 50% EtOH in Hexanes:DCM (3:1) (0.5% 2M NH₃ MeOH). ²⁶Racemate purification: Reverse phase chromatography: Column, C18; eluting with 30% to 35% ACN in H₂O (0.1% NH₄OH), 254 nm. ²⁷Column: Chiral ART Cellulose-SC, 2*25 cm, 5 μm; eluting with 30% MeOH in hexanes:MTBE 1:1) (2M NH₃ MeOH); flow rate 20 mL/min; 256/212 nm. ²⁸Racemate purification: Prep-TLC (EtOAc). ²⁹Column: CHIRALPAK IG, 2*25 cm, 20 μm; eluting with 50% EtOH in hexanes:DCM (5:1) (0.5% 2M NH₃ MeOH). ³⁰Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 60% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ³¹Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 50% iPrOH in hexanes (10 mM NH₃ MeOH); flow rate 25 mL/min; 254/270 nm. ³²Kinetex EVO C18 Column, 21.2*150, 5 μm; eluting with 30% to 52% ACN in H₂O (10 mmol/L NH₄HCO₃); flow rate: 25 mL/min; 254/220 nm. ³³Column: CHIRALPAK IC, 2*25 cm, 5 μm; eluting with 20% EtOH in MTBE (10 mM NH₃ MeOH), flow rate:20 mL/min; 250/325 nm. ³⁴Racemate purification: Column: )(Bridge Prep C18 OBD, 19*150 mm, 5 m; eluting with 34% to 45% ACN in H₂O (10 mmol/L NH₄OH). ³⁵Column: CHIRALPAK IF, 2*25 cm, 5 m, eluting with 15% EtOH in MTBE (10 mM NH3-MeOH); flow rate: 20 mL/min; 254/325. ³⁶Racemate purification: Reverse phase chromatography: Column, C18; eluting with 50% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ³⁷Column: CHIRALPAK IA-3, 4.6*50 cm, 3 μm, eluting with 50% EtOH in MTBE (0.1% diethylamine); flow rate: 1 mL/min. ³⁸Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 60% ACN in H₂O (0.1% FA), 254 nm. ³⁹Column: CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 50% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min; 254/325. ⁴⁰Racemate purification: Reverse phase C18 chromatography eluting with 0% to 100% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁴¹Chiral ART Cellulose-SB, 2*25 cm, 5 μm; eluting with 30% EtOH in hexanes:MTBE (1:1) (0.5% NH₃ MeOH)); flow rate 20 mL/min; 254/320 nm. ⁴²Column: CHIRALPAK IA, 2*25 cm, 5 μm; eluting with 50% EtOH in hexanes:MTBE (1:1) (0.5% 2M NH₃ MeOH). ⁴³Racemate purification: Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm; eluting with 32% to 48% ACN in H₂O (10 mmol/L NH₄HCO₃). ⁴⁴Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 50% EtOH in hexanes:DCM (5:1) (0.1% diethylamine); flow rate: 18 mL/min; 254/220. ⁴⁵Racemate purification: Reverse phase chromatography: Column, C18; eluting with 60% to 70% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁴⁶Column: CHIRALPAK IA, 2*25 cm, 5 μm, eluting with 50% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min., 254/320 nm. ⁴⁷Racemate purification: Reverse phase chromatography: Column, C18; eluting with 30% to 50% ACN in H₂O (0.1% NH₄OH), 254 nm. ⁴⁸Column: CHIRALPAK IA, 2.12*15 cm, 5 μm, eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min., 254/300 nm. ⁴⁹Racemate purification: Reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H₂O (NH₄HCO₃), 254 nm. ⁵⁰Column: CHIRALPAK IA, 2*25 cm, 20 μm; eluting with 50% EtOH in hexanes:DCM (5:1) (0.5% 2M NH₃ MeOH), flow rate: 18 mL/min., 254/220 nm. ⁵¹Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; eluting with 10% EtOH in hexanes:DCM (5:1)(0.5% 2M NH₃—MeOH, flow rate:20 mL/min., 254/210 nm. ⁵²Racemate purification: Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm; eluting with 21% to 43% ACN in H₂O (10 mmol/L NH₄HCO₃). ⁵³Column: CHIRALPAK IA, 2*25 cm, 20 μm; eluting with 30% EtOH in hexanes:DCM (5:1) (0.5% 2M NH₃ MeOH), flow rate: 20 mL/min., 254/220 nm. ⁵⁴Racemate purification: Reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H₂O (0.1% FA), 254 nm. ⁵⁵Column: Lux Cellulose-4, 2.12*25 cm, 5 μm; eluting with 90% ACN in H₂O; flow rate 25 mL/min; 254/220 nm. ⁵⁶Column: CHIRALPAK IA, 2*25 cm, 5 μm, eluting with 50% EtOH in hexanes:MTBE (0.5% 2M NH₃ MeOH); flow rate: 18 mL/min; 250/210. ⁵⁸Column: CHIRALPAK IA, 2.12*15 cm, 5 μm, eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min., 254/220 nm. ⁵⁹Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 70% ACN in H₂O (0.05% NH₄HCO₃), 254 nm. ⁶⁰Column: CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min; 254/220. ⁶¹Racemate purification: Reverse phase chromatography: Column, C18; eluting with 47% to 53% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁶²Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 20% iPrOH in hexanes:DCM (5:1) (0.5% 2M NH₃ MeOH); flow rate: 20 mL/min; 254/210. ⁶³Racemate purification: Reverse phase chromatography: Column, C18; eluting with 25% to 55% ACN in MTBE, 254 nm. ⁶⁴Column: NB Lux i-Cellulose-5, 2.12*25 cm, 5 μm; eluting with 20% EtOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 254/320 nm. ⁶⁵Racemate purification: Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm; eluting with 43% to 53% MeOH in H₂O (10 mmol/L NH₄HCO₃). ⁶⁶Column: Lux Cellulose-4, 2.12*25 cm, 5 μm; eluting with 80% ACN in H₂O; flow rate 25 mL/min; 254/220 nm. ⁶⁷Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 20% EtOH in hexanes:DCM (3:1) (0.5% 2M NH₃ MeOH); flow rate: 20 mL/min; 254/210. ⁶⁸Chiral ART Cellulose-SB, 2*25 cm, 5 μm; eluting with 10% EtOH in MTBE (10 mM NH₃ MeOH)); flow rate 20 mL/min; 254/320 nm. ⁶⁹Column: CHIRALPAK IA, 2*25 cm, 5 μm; eluting with 50% EtOH in hexanes:DCM (3:1) (0.5% 2M NH₃ MeOH). ⁷⁰Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 250/215 nm. ⁷¹Column: CHIRALPAK IA, 2*25 cm, 5 μm, eluting with 30% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min., 254/215 nm. ⁷²Racemate purification: Reverse phase chromatography: Column, C18; eluting with 36% to 40% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁷³Column CHIRALPAK IA, 2.12*15 cm, 5 μm, eluting with 20% EtOH in MTBE (10 mM NH₃ MeOH); flow rate: 20 mL/min., 254/220 nm. ⁷⁴Racemate purification: Reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H₂O, 254 nm. ⁷⁵Column: Chiral ART Cellulose-SC, 2*25 cm, 5 μm; eluting with 40% EtOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 250/215 nm. ⁷⁶Racemate purification: Reverse phase chromatography: Column, C18; eluting with 50% to 60% ACN in H₂O, 254 nm. ⁷⁷Column:(R,R)-WRELK-01-Kromasil, 2.11*25 cm, 5 μm; eluting with 50% EtOH in hexanes:DCM (3:1)(0.5% 2M NH₃ MeOH, flow rate 20 mL/min; 254 nm. ⁷⁸Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 50% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁷⁹Racemate purification: Reverse phase chromatography: Column, C18; eluting with 85% to 90% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁸⁰Racemate purification: Reverse phase chromatography: Column, C18; eluting with 30% to 70% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁸¹Racemate purification: Reverse phase chromatography: Column, C18; eluting with 10% to 50% ACN in H₂O (0.1% NH₄OH), 254 nm. ⁸³Column, CHIRAL ART Amylose-SA, 2*25 cm, 5 μm, eluting with hexanes:DCM (5:1) (0.5% 2M NH₃ MeOH) in 20% EtOH, flow rate 20 mL/min, 254 nm. ⁸⁴Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 50% MeOH in MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 244/210 nm. ⁸⁵Racemate purification: Reverse phase chromatography: Column, C18; eluting with 40% to 70% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁸⁶Column: CHIRALPAK IE, 2*25 cm, 5 μm, eluting with 20% MeOH in 1:1 Hex:MTBE (1:1)(0.5% 2M NH₃ MeOH); flow rate: 20 mL/min; 246/310. ⁸⁷Column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; eluting with 40% MeOH in Hex:MTBE (10 mM NH₃ MeOH); flow rate 20 mL/min; 254/314 nm.; 254/210. ⁸⁸Racemate purification: Reverse phase chromatography: Column, C18; eluting with 55% to 60% ACN in H₂O (0.1% NH₄HCO₃), 254 nm. ⁸⁹Column: CHIRALPAK ID, 2*25 cm, 5 μm; eluting with 10% i-PrOH in Hex: DCM (1:1) (diethylamine); flow rate 20 mL/min; 220/254 nm. ⁹⁰Column: CHIRALPAK IA, 21.2*250 cm,; eluting with 50% MeOH in CO₂; flow rate 80 ml/min; 225 nm. ⁹¹Column: Chiralcel-OD-H, 21*250 mm; eluting with a 65% CO₂ in MeOH; flow rate 80 mL/min; UV at 225 nm. ⁹²Column: Chiralpak AD-H, 250 x 21 mm; eluting with an 65% CO₂ in EtOH (0.5% DMEA); flow rate 70 mL/min; UV at 225 nm. ⁹³Column: Chiralpak AD-H, 250 x 21 mm; eluting with an 50% CO₂ in EtOH (0.5% DMEA); flow rate 70 mL/min; 254 nm. ⁹⁴Purified by reverse phase chromatography, C18 column, eluting with 40% to 50% ACN in H₂O. ⁹⁵Column: NB Lux i-Cellulose-5, 2.12*25 cm, 5 μm; Mobile eluting with 30% MeOH in MtBE (10 mM NH₃ MeOH); Flow rate: 20 mL/min; 220/320 nm. ⁹⁶Column: CHIRALPAK IF, 2*25 cm, 5 μm, eluting with 30% i-PrOH in hexanes:DCM (3:1) (0.5% 2M NH₃ MeOH); flow rate: 20 mL/min; 254/220. ⁹⁷1H NMR (400 MHz, Chloroform-d) δ 8.47 (d, 1H), 8.25 (d, 1H), 7.86 (s, 1H), 7.61-7.52 (m, 1H), 7.46-7.37 (m, 1H), 6.74 (s, 1H), 5.62-5.56 (m, 1H), 4.56-4.44 (m, 1H), 4.20-04.05 (m, 2H), 3.42-3.25 (m, 4H), 2.98-2.67 (m, 6H), 2.64-2.44 (m, 4H), 2.32 (s, 3H). ⁹⁹Racemate purification: flash reverse phase chromatography: Column: XB-C18, 250*50 mm, 10 μm; eluting with 20% to 50% CAN in aq. 10 mmol NH4HCO3; Flowrate:100mL/min; 254/220 nm. ¹⁰⁰Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; eluting with 50% EtOH in Hex (0.1% 2M NH₃ MeOH); Flow rate: 40 mL/min; 244/280 nm. ¹⁰¹Purified by reverse phase chromatography, C18 column, eluting with 50% to 60% ACN in H₂O. ¹⁰²CHIRALPAK IA, 2*25 cm, 5 μm; eluting with 15% MeOH in hexanes:MTBE (1:1) (0.5% 2M NH₃ MeOH); 286/214 nm. ¹⁰³Chiralpak IA, 21.2 x 250 mm column, eluting with 60% 60% CO₂, in 40% MeOH (0.5% DMEA): 80 mL/min. ¹⁰⁴Purified by reverse phase chromatography, C18 column ¹⁰⁵Column: Chiralpak AS-H, 150 x 21 mm; eluting with an 75% CO₂ in EtOH; flow rate 80 mL/min; UV at 250 nm.

Example 166 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl)methoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 1 and Example 167 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl)methoxy]imidazo[1,2-a]pyridine-3-carbonitrile, Isomer 2

To 3-cyano-5-[(5-fluoropyridin-2-yl)(1-methoxycyclopropyl)methoxy]imidazo[1,2-a]pyridin-7-ylboronic acid (400 mg, 1.05 mmol), 4-(4-bromo-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carbonitrile (424 mg, 1.57 mmol), XPhos (49.90 mg, 0.105 mmol) and K₃PO₄ (667 mg, 3.14 mmol) in dioxane (5 mL) and H₂O (1 mL) is added XPhos Pd G3 (88.60 mg, 0.105 mmol) in portions at RT under N₂. The reaction is stirred for 2 hr at 60° C. Upon cooling to RT, the reaction is diluted with H₂O (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layers are washed with brine (2×20 mL), dried over Na₂SO₄, and concentrated in vacuo. The residue is purified by Prep-TLC (EtOAc) to afford 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl)methoxy]imidazo[1,2-a]pyridine-3-carbonitrile as a yellow solid (130 mg, 24%). ES/MS m/z 528.2 [M+H]⁺. 7-[1-(1-Cyano-4-piperidyl)-5-methyl-triazol-4-yl]-5-[(5-fluoro-2-pyridyl)-(1-methoxycyclopropyl)methoxy]imidazo[1,2-a]pyridine-3-carbonitrile is subjected to prep-chiral-HPLC: Column: CHIRALPAK IF, 2*25 cm, 5 m; eluting with 35% MeOH in hexanes:MTBE (1:1) (0.5% 2M NH₃-MEOH), 320/254 nm; to afford the title compound, Isomer 1, t_((R)) is 9.04 min (38.9 mg, 32.4%) with 97.6% ee, ES/MS m/z 528.15 [M+H]⁺ and the title compound, Isomer 2, t_((R)) is 10.79 min (18.9 mg, 15.8%) with 97.6% ee, ES/MS m/z 528.40 [M+H]⁺.

Example 168 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile

A solution of 4-oxopiperidine-1-carbonitrile (80 mg, 0.65 mmol) and 6-[1-(azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.32 mmol) in MeOH (3 mL) is treated with NaBH₃CN (102 mg, 1.62 mmol) and stirred overnight at RT under N₂. The mixture is quenched with H₂O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts are concentrated under reduced pressure. The crude product (100 mg) is purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD, 19*150 mm, 5 μm; eluting with a gradient of 30% to 50% ACN in H₂O (10 mmol/L NH₄HCO₃) to give the title compound as a white solid (26.3 mg, 19.4%). ES/MS m/z 417.30 [M+H]⁺.

Example 169 4-(4-[3-Cyano-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

A solution of 6-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]-4-[(1R)-1-(pyridin-2-yl)ethoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (200 mg, 0.47 mmol), DIEA (603 mg, 4.67 mmol) in DCM (8 mL) is treated with BrCN (59 mg, 0.56 mmol) and stirred for 2 hrs at RT under N₂. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18 silica; eluting with a gradient of 30% to 40% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (90.5 mg, 42.8%). ES/MS m/z 454.15 [M+H]⁺.

Example 170 4-(4-[3-Cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carbonitrile

A stirred solution of 5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]-7-[5-methyl-1-(piperidin-4-yl)-1,2,3-triazol-4-yl]imidazo[1,2-a]pyridine-3-carbonitrile.HCl (85.0 mg, 0.19 mmol) and DIEA (246.0 mg, 1.90 mmol) in DCM (5.0 mL) is treated with BrCN (24.2 mg, 0.23 mmol) and stirred for 30 min at 0° C. under N₂. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 3000 to 500% ACN in H₂O (0.10% NH₄HCO₃) to give the title compound as a white solid (32.9 mg, 36.20). ES/MS m/z 472.10 [M+H]⁺.

The following compounds are prepared essentially as described for 4-(4-[3-cyano-5-[(1R)-1-(5-fluoropyridin-2-yl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-1,2,3-triazol-1-yl)piperidine-1-carbonitrile using the appropriate reagents, adjusting reaction time to allow for completion of the reaction, and altering the purification system as appropriate. Temperature is varied from 0° C. to RT.

TABLE 64 ES/MS Ex. m/z Elution No. Chemical name Structure [M + H]⁺ Gradient 171 2-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)- 7- azaspiro[3.5]nonane- 7-carbonitrile

402.2 40-50% 172 3-[4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidin-1-yl]- 2,2- dimethylazetidine-1- carbonitrile, Isomer 1

445.30 18-22% 173 3-[4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidin-1-yl]- 2,2- dimethylazetidine-1- carbonitrile, Isomer 2

445.35 40-50% 174 (3R)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

362.1 33-37% B 175 4-(4-[3-Cyano-4- [(1R)-1-(pyridin-2- yl)propoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

467.2 50-60% 176 4-(4-[3-Cyano-4- [(1R)-1-(1- methylpyrazol-3- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

456.20 40-50% 177 (2R,4S)-4-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1-yl)- 2-methylpyrrolidine- 1-carbonitrile

361.95 50-55% 178 4-[4-(3-Cyano-4- [[(2R)-1,1,1- trifluoropropan-2- yl]oxy]pyrazolo[1,5- a]pyridin-6-yl)-5- methylpyrazol-1- yl]piperidine-1- carbonitrile

444.15 30-70% 179² 4-[3-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-3,3- difluoropiperidine-1- carbonitrile, Isomer 1

453.2 36-42% B 180¹ 4-[3-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-3,3- difluoropiperidine-1- carbonitrile, Isomer 2

453.2 33-46% B 181 4-(4-[3-Cyano-4- isopropoxypyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1-yl) piperidine-1- carbonitrile

390.20 182 (3S)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

362.20 40-60% 183³ 6-(1-((1R,3r,5S)-8- Cyano-8- azabicyclo[3.2.1]octan- 3-yl)-5-methyl-1H- pyrazol-4-yl)-4- methoxypyrazolo[1,5- a]pyridine-3- carbonitrile

388.10 184 6-(1-((1R,3s,5S)-8- Cyano-8- azabicyclo[3.2.1]octan- 3-yl)-5-methyl-1H- pyrazol-4-yl)-4- methoxypyrazolo[1,5- a]pyridine-3- carbonitrile

388.15 40-60% 185 6-[1-[1-[(3S)-1- Cyanopyrrolidin-3- yl]-4-piperidyl]-5- methyl-pyrazol-4-yl]- 4-methoxy- pyrazolo[1,5- a]pyridine-3- carbonitrile

431.15 25-45% 186 4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-3- methylpyrazol-1- yl)piperidine-1- carbonitrile

362.1 40-60% 187 4-(4-[3-Cyano-4- [(1R)-1-(3- fluoropyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

471.10 40-60% 188 4-(4-[3-Cyano-4- [(1R)-1-(pyrazin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

453.95 36-40% 189 4-(4-[3-Cyano-4- [(1R)-1-(2- methylpyrazol-3- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

456.5 40-45% 190 4-(4-[3-Cyano-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

453.1 10-50% 191⁴ 6-(1-((3R,5S)-1- Cyano-5- methylpyrrolidin-3- yl)-5-methyl-1H- pyrazol-4-yl)-4- methoxypyrazolo [1,5-a]pyridine-3- carbonitrile

362.15 30-46% B 192 6-(1-((3S,5S)-1- cyano-5- methylpyrrolidin-3- yl)-5-methyl-1H- pyrazol-4-yl)-4- methoxypyrazolo [1,5-a]pyridine-3- carbonitrile

361.95 38-42% 193⁵ 4-(4-[3-Cyano-4- [(1R)-1- cyclopropylethoxy] pyrazolo[1,5-a]pyridin- 6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

416.2 42-62% B 194 4-[4-(3-Cyano-4- [[(2S)-1,1,1- trifluoropropan-2- yl]oxy]pyrazolo[1,5- a]pyridin-6-yl)-5- methylpyrazol-1- yl]piperidine-1- carbonitrile

444.15 30-70% 195 4-(4-[3-cyano-4- [(1R)-1- cyclobutylethoxy] pyrazolo[1,5-a]pyridin- 6-yl]-5- methylpyrazol-1- yl)piperidine-1- carbonitrile

430.0 60-65% 196⁶ 4-(4-[3-Cyano-4-iso- propoxypyrazolo[1,5-a] pyridin-6-yl]-5-methyl- 1,2,3-triazol-1-yl) piperidine-1- carbonitrile

391.2 None 197 4-(4-[3-Cyano-4- [(1R)-1- cyclobutylethoxy] pyrazolo[1,5-a]pyridin- 6-yl]-5-methyl-1,2,3- triazol-1- yl)piperidine-1- carbonitrile

431.0 42-47% 198⁵ 4-(4-[3-Cyano-4- [(1R)-1- cyclopropylethoxy] pyrazolo[1,5-a]pyridin- 6-yl]-5-methyl-1,2,3- triazol-1- yl)piperidine-1- carbonitrile

417.2 36-61% B 199 4-(4-[3-Cyano-4- [(1S)-2,2,2-trifluoro- 1-(pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

508.05 40-60% 200 4-(4-[3-Chloro-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

463.05 43-48% 201 4-(4-[3-Cyano-5- [(1R)-1-(pyridin-2- yl)ethoxy]imidazo [1,2-a]pyridin-7-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

454.05 33-37% 202 4-(4-[3-Cyano-4- [(1R)-1- cyclohexylethoxy] pyrazolo[1,5-a]pyridin- 6-yl]-5-methyl-1,2,3- triazol-1- yl)piperidine-1- carbonitrile

459.15 57-57% 203 (3R)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)pyrrolidine-1- carbonitrile

348.9 30-40% 204 (3S)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)pyrrolidine-1- carbonitrile

348.9 30-50% 205 4-(4-[3-Cyano-4- [(1R)-1-phenyl- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

453.20 30-50% 206 4-(4-[3-Cyano-4- [(1S)-2,2,2-trifluoro- 1-phenyl- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

507.4 5-100% 207 4-(4-[3-Cyano-4- [[(7R)-6,7-dihydro- 5H- cyclopenta[b]pyridin- 7-yl]oxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-1,2,3- triazol-1-yl) piperidine-1- carbonitrile

466.2 30-50% 208¹ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- pyrazol-4-yl]-5- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

481.15 36-37% 209 7-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(1R)- 1-(2- pyridyl)propoxy] imidazo [1,2-a]pyridine-3- carbonitrile

471.3 45-55% 210⁴ 7-[1-(1-cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[(1R)- 1-(2-pyridyl) propoxy]imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 2

468.05 33-52% 211⁷ 7-[1-(1-Cyano-4- piperidyl)-5-methyl- triazol-4-yl]-5-[[(7R)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 7-yl]oxy]imidazo [1,2-a]pyridine-3- carbonitrile

466.3 19-50% 212⁴ 7-[1-(7-Cyano-7- azaspiro[3.5]nonan-2- yl)-5-methyl-triazol- 4-yl]-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

494.30 32-52% 213⁸ 4-[4-[4-Methoxy-3- (trifluoromethyl)pyrazolo [1,5-a]pyridin-6- yl]-5-methyl-pyrazol- 1-yl]piperidine-1- carbonitrile

404.8 10-100% 214 4-[4-[4-[(1R)-1-(5- Fluoro-2- pyridyl)ethoxy]-3- (hydroxymethyl)pyrazolo [1,5-a]pyridin-6- yl]-5-methyl-triazol- 1-yl]piperidine-1- carbonitrile

476.8 10-100% ¹Column: Kinetex EVO C18, 21.2*150, 5 μm, mobile phase A: H₂O (0.05% NH₃H₂O), mobile phase B: ACN. ²Column: XBridge Shield RP18 OBD, 19*150 mm, 5 μm, mobile phase A: H₂O (0.05% NH₃H₂O), mobile phase B: ACN. ³Crude product is re-crystallized from MTBE (20 mL). ⁴Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm, mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: ACN. ⁵Column: Gemini-NX C18 AXAI Packed, 21.2*150 mm, 5 μm, mobile phase A: H₂O (0.1% FA), mobile phase B: ACN. ⁶Prep-TLC (PE:EtOAc 1:1) followed by trituration in Et₂O (10 mL), filtration, and washing with Et₂O (3 × 15 mL). ⁷Column: SunFire Prep C18 OBD, 19 × 150 mm, 5 μm, mobile phase A: H₂O (0.1% FA), Mobile Phase B: ACN.

Example 215 (3S)-3-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile

A solution of 4-methoxy-6-(5-methyl-1-[1-[(3S)-piperidin-3-yl]azetidin-3-yl]pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (100 mg, 0.26 mmol) and DIEA (330 mg, 2.55 mmol) in DCM (2 mL) is treated with BrCN (27 mg, 0.255 mmol) and stirred for 2 hrs at −60° C. under N₂. The mixture is warmed to RT, quenched with sat. NaHCO₃ (aq.) (10 mL) and extracted with DCM (2×15 mL). The combined organic extracts are washed with brine (2×10 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 44% to 49% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (30 mg, 28.20%). ES/MS m/z 417.20 [M+H]⁺.

The following compounds are prepared essentially as described for (3S)-3-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile using the appropriate reagents, adjusting reaction time to determine completion of the reaction, and adjusting the purification system as appropriate. Temperature is varied from −60° C. to −75° C.

TABLE 65 ES/MS Ex. m/z Elution No. Chemical name Structure [M + H]⁺ Gradient 216 (3R)-3-[3-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile

417.15 30-70% 217¹ (2S,4R)-4-[3-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-2- methylpyrrolidine-1- carbonitrile

417.2 25-48% B 218¹ (3R)-3-[3-(4-[3- Cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carbonitrile

494.2 27-34% B 219² (3S)-3-[3-(4-[3- Cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carbonitrile

493.35 33-47% B 220 (2R,4R)-4-[3-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1-yl]-2- methylpyrrolidine-1- carbonitrile

417.15 40-60% 221 (3S)-3-[3-(4-[3- Cyano-4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carbonitrile

494.30 41-45% 222 (3R)-3-[3-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carbonitrile

403.3 25-40% B 223¹ (3S)-3-[3-(4-[3- Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)azetidin-1- yl]pyrrolidine-1- carbonitrile

403.1 20-50% B 224² 6-[1-[1-[(3S)-1- Cyanopyrrolidin-3- yl]azetidin-3-yl]-5- methyl-pyrazol-4-yl]- 4-[[(1R)-1-(2- pyridyl)ethyl]amino] pyrazolo[1,5- a]pyridine-3- carbonitrile

493.2 33-47% 225³ 6-(1-(1-(6-cyano-6- azabicyclo[3.2.1]octan- 3-yl)azetidin-3-yl)- 5-methyl-1H-pyrazol- 4-yl)-4- methoxypyrazolo[1,5- a]pyridine-3- carbonitrile

443.1 20-50% 226¹ 7-[1-[1-(7-Cyano-7- azabicyclo[2.2.1]heptan- 2-yl)azetidin-3- yl]-5-methyl-pyrazol- 4-yl]-5-[(1R)-1-(2- pyridyl)ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

520.10 28-44% ¹Column: XBridge Prep C18 OBD, 19*150 mm, 5 μm, mobile phase A, H₂O (10 mmol/L NH₄HCO₃), mobile phase B, ACN. ²Column: XBridge Shield RP18 OBD, 19*150 mm, 5 μm, mobile phase A, H₂O (10 mmol/L NH₄HCO₃), mobile phase B, ACN. ³Column: Galaksil UP C18, 8 μm; mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: ACN.

Example 227 4-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carbonitrile

A solution of 4-methoxy-6-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (60 mg, 0.18 mmol) and K₂CO₃ (74 mg, 0.53 mmol) in DMF (1 mL) is treated with BrCN (23 mg, 0.21 mmol) and stirred for 16 hrs at 80° C. under N₂. The mixture is cooled to RT, quenched with H₂O (10 mL), and extracted with EtOAc (3×5 mL). The combined organic extracts are washed with brine (3×15 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by Prep-HPLC with the following conditions: Column, Kinetex EVO C18 Column, 21.2*E150, 5 μm; eluting with a gradient of 30% to 45% ACN in H₂O (0.05% N₃H₂O) to give the title compound as a white solid (9 mg, 14%). ES/MS m/z 362.15 [M+H]⁺.

The following compounds are prepared essentially as described for 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carbonitrile adjusting reaction time to allow for completion of the reaction and adjusting the purification system as appropriate. Temperature is varied from 80° C. to 100° C.

TABLE 66 ES/MS Ex. m/z Elution No. Chemical name Structure [M + H]⁺ Gradient 228 3-[4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)piperidin-1- yl]azetidine-1- carbonitrile

417.2  5-45% B 229¹ (3R)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)pyrrolidine-1- carbonitrile

348.15 50-70% 230¹ (3S)-3-(4-[3-Cyano- 4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methylpyrazol-1- yl)pyrrolidine-1- carbonitrile

348.20 40-55% 231 4-(4-[3-Cyano-4- methoxypyrazolo[1,5- a]pyridin-6-yl]-5- methyl-1,2,3-triazol- 1-yl)piperidine-1- carbonitrile

363.15 20-30% B ¹Reverse Combi-flash chromatography with the following conditions: C18; H₂O (0.1% FA) in ACN.

Example 232 3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azetidine-1-carbonitrile

A solution of 6-[1-(azetidin-3-yl)-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (80 mg, 0.26 mmol), BrCN (33 mg, 0.31 mmol) and Cs₂CO₃ (254 mg, 0.78 mmol) in DMF (5 mL) is stirred for 2 hrs at 80° C. The mixture is cooled to RT and purified by reverse Combi-flash chromatography with the following conditions: Column, C18; 10-50% ACN in H₂O to give the title compound as an off-white solid (20.6 mg, 23.8%). ES/MS m/z 334.10 [M+H]⁺.

Example 233 4-[3-[4-[3-Chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridin-7-yl]-5-methyl-triazol-1-yl]azetidin-1-yl]piperidine-1-carbonitrile

A mixture of 7-[1-(Azetidin-3-yl)-5-methyl-triazol-4-yl]-3-chloro-5-[(1R)-1-(2-pyridyl)ethoxy]imidazo[1,2-a]pyridine TFA (100.00 mg), 4-oxopiperidine-1-carbonitrile (90.86 mg, 0.73 mmol) and AcOH (1.47 mg, 0.02 mmol) in MeOH (5.00 mL) is stirred at 50° C. for 30 min under N₂. Upon cooling to RT, NaBH₃CN (23.00 mg, 0.37 mmol) is added in portions. The resulting mixture is stirred at 50° C. for 2 hr then concentrated in vacuo. The residue is purified by Prep-HPLC with the following conditions: Column: Kinetex EVO C18 Column, 21.2*150, 5 μm; eluting with 21% to 47% ACN in H₂O (0.05% NH₄OH); 254/220 nm; to give the title compound as a white solid (16.3 mg, 12.9%). ES/MS m/z 518.20 [M+H]⁺.

Example 234 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile

A solution of 6-[1-(azetidin-3-yl)pyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (100.00 mg), 4-oxopiperidine-1-carbonitrile (210.90 mg, 1.70 mmol) and AcOH (2.04 mg, 0.034 mmol) in MeOH (3.00 mL) is stirred for 40 min at 50° C. under N₂. The solution is treated with NaBH₃CN (42.70 mg, 0.68 mmol) at RT, and stirred for 1 hr at 50° C. The mixture is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 60% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (23.8 mg, 17.40%). ES/MS m/z 403.25 [M+H]⁺.

The following compounds are prepared essentially as described for 4-[3-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile using the appropriate reagents, adjusting reaction time to determine completion of the reaction, and adjusting the purification system as appropriate.

TABLE 67 ES/MS Ex. m/z Elution No. Chemical name Structure [M + H]⁺ Gradient 235 4-[3-(4-[3-Cyano- 4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6- yl]-5-methyl- 1,2,3-triazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile

509.2 30-50% 236 4-[3-(4-[3-Cyano- 4-[(1R)-1- (pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6- yl]-5- methylpyrazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile

508.3 40-44% 237¹ 4-[3-(4-[3-Cyano- 4- methoxypyrazolo [1,5-a]pyridin-6- yl]-5-methyl- 1,2,3-triazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile. FA

418.15 10-22% B 238² 4-[3-(4-[3-Cyano- 5-[(1R)-1- (pyridin-2- yl)ethoxy]imidazo [1,2-a]pyridin-7- yl]-5-methyl- 1,2,3-triazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile

509.05 25-40% B 239³ 4-[3-(4-[3-cyano- 4- isopropoxypyrazolo [1,5-a]pyridin- 6-yl]-5-methyl- 1,2,3-triazol-1- yl)azetidin-1- yl]piperidine-1- carbonitrile

446.10 32-40% B ¹SunFire Prep C18 OBD Column; mobile phase A: H₂O (0.1% FA), mobile phase B: ACN. ²XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm, mobile phase A: H₂O (0.05% NH₃H₂O), Mobile Phase B: ACN. ³XBridge Prep C18 OBD Column, 19*150 mm, 5 μm; mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: ACN.

Example 240 4-[3-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-3-methylpyrazol-1-yl)azetidin-1-yl]piperidine-1-carbonitrile

AcOH (1.95 mg, 0.03 mmol) is added dropwise and NaBH₃CN (61.14 mg, 0.97 mmol) is added in portions to a mixture of 6-(1-(azetidin-3-yl)-3-methyl-1H-pyrazol-4-yl)-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile.TFA (90.00 mg, 0.32 mmol) and 4-oxopiperidine-1-carbonitrile (201.31 mg, 1.62 mmol) in MeOH (3.00 mL) at RT under N₂. The mixture is stirred for 1 hr at 50° C. The reaction is quenched with NH₄Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic extracts are washed with brine (2×100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 40% to 50% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as a white solid (40.8 mg, 30%). ES/MS m/z 417.1 [M+H]⁺.

Example 241 4-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl)piperidine-1-carbonitrile

BrCN (42.71 mg, 0.40 mmol) is added in portions to a stirred solution of 4-methoxy-6-[1-(piperidin-4-yl)pyrazol-4-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile.HCl (100.00 mg, 0.31 mmol) and DIEA (400.91 mg, 3.10 mmol) in DCM (5.00 mL), and the mixture is stirred for 1 hr at RT under N₂. The mixture is quenched with H₂O (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts are washed with sat. NaHCO₃ (20 mL) and brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: column, C18; eluting with a gradient of 45% to 55% ACN in H₂O to give the title compound as a white solid (41.7 mg, 38.70%). ES/MS m/z 348.25 [M+H]⁺.

The following compounds are prepared essentially as described for 4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]pyrazol-1-yl)piperidine-1-carbonitrile using the appropriate reagents, adjusting reaction time to determine completion of the reaction, and adjusting the purification system as appropriate.

TABLE 68 ES/M Ex. m/z Elution No. Chemical name Structure [M + H]⁺ Gradient 242 4-(4-[3-Cyano-4- [(1R)-1-(pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carbonitrile

453.2 50-60% 243 (2R,4R)-4-(4-[3- Cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)-2-methyl pyrrolidine-1- carbonitrile

362.10 10-60% 244¹ 4-(4-[3-Cyano-4- [(1S)-1-(pyridin-2- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carbonitrile

453.15 31-45% B 245 4-(4-[3-Cyano-4- [(1R)-1-(oxan-4- yl)ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidine-1- carbonitrile

460.2 20-50% 246 4-(4-[3-Cyano-4- [(3-fluoropyridin-2- yl)methoxy]pyrazolo [1,5-a]pyridin-6- yl]-5-methyl pyrazol-1- yl)piperidine-1- carbonitrile

457.25 40-43% 247² (3R)-3-[4-(3- Cyano-4-[[(1R)-1- (pyridin-2- yl)ethyl]amino] pyrazolo[1,5- a]pyridin-6-yl)-5- methylpyrazol-1- yl]pyrrolidine-1- carbonitrile

438.1 30-35% 248 (3R)-3-[4-(4-[3- Cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl]- 5-methylpyrazol-1- yl)piperidin-1- yl]pyrrolidine-1- carbonitrile

431.2 30-40% 249³ 4-[4-(3-Cyano-4- [[2-(pyridin-2- yl)propan-2- yl]oxy]pyrazolo [1,5-a]pyridin-6-yl)- 5- methylpyrazol-1- yl]piperidine-1- carbonitrile

467.2 30-48% B 250⁴ (3S)-3-[4-(3- Cyano-4-[[(1R)-1- (pyridin-2- yl)ethyl]amino] pyrazolo[1,5- a]pyridin-6-yl)-5- methylpyrazol-1- yl]pyrrolidine-1- carbonitrile

438.20 251⁵ 4-[4-[5-[(1R)-1-(5- fluoro-2- pyridyl)ethoxy]-3- methyl-imidazo [1,2-a]pyridin-7- yl]-5-methyl- triazol-1-yl] piperidine-1- carbonitrile

461.25 252⁶ 7-[1-(7-cyano-7- azaspiro[3.5]nonan- 2-yl)-5-methyl- triazol-4-yl]-5- [(1R)-1-(5-fluoro- 2-pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

512.25 50-55% 253³ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[2-methoxy- 1-(2- pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

484.05 31-50% 254¹ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(3- fluoro-2- pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

472.1 17-45% 255⁷ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(2- fluorophenyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

471.1 50-68% 256⁶ 4-[4-[4-[(1R)-1-(2- Cyanophenyl)ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-pyrazol-1- yl]piperidine-1- carbonitrile

452.15 10-50% 257¹ 7-[1-(1- Cyanoazepan-4-yl)- 5-methyl-triazol-4- yl]-5-[(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

468.1 28-40% 258⁸ 6-[1-[1-(7-Cyano- 7- azabicyclo[2.2.1] heptan-2-yl)azetidin- 3-yl]-5-methyl- pyrazol-4-yl]-4- methoxy-pyrazolo [1,5-a]pyridine-3- carbonitrile

429.20 50-70% 259⁹ 7-[1-[(3S)-1- Cyano-3- piperidyl]-5- methyl-triazol-4- yl]-5-[(1R)-1-(5- fluoro-2-pyridyl) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

472.35 260⁸ 7-[1-[(3R)-1- Cyano-3- piperidyl]-5- methyl-triazol-4- yl]-5-[(1R)-1-(5- fluoro-2-pyridyl) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

472.20 30-45% 261^(6,10) 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[[(1R)-1-(5- fluoro-2-pyridyl) ethyl]amino] imidazo[1,2- a]pyridine-3- carbonitrile

471.2 30-38% 262⁶ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-pyrazol-4- yl]-5-[[(1R)-1-(2- pyridyl)ethyl]amino] imidazo[1,2- a]pyridine-3- carbonitrile

452.30 40-60% 263⁸ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1- pyrimidin-4- ylethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

455.20 — 264⁶ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[2,2- dimethyl-1-(2- pyridyl)propoxy] imidazo[1,2- a]pyridine-3- carbonitrile, Isomer 1

496.3 30-50% 265¹¹ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(2,6- difluorophenyl) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

489.1 10-50% 266¹¹ 5-[(1R)-1-(2- Chloro-4-fluoro- phenyl)ethoxy]-7- [1-(1-cyano-4- piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile

504.2 0-100% 267¹² 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(5- fluoro-3-methyl-2- pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

486.2 30-50% 268¹³ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(5-fluoro-2- pyridyl)methoxy] imidazo[1,2- a]pyridine-3- carbonitrile

458.2 269¹⁴ 5-[(1R)-1-(5- Chloro-2- pyridyl)ethoxy]-7- [1-(1-cyano-4- piperidyl)-5- methyl-triazol-4- yl]imidazo[1,2- a]pyridine-3- carbonitrile

488.15 270¹⁵ 6-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-4-[(1R)-1-(5- fluoro-2-pyridyl) ethoxy]pyrazolo[1,5- a]pyridine-3- carbonitrile

472.2 33-52% 271 4-[4-[4-[(1R)-1-(5- Fluoro-2- pyridyl)ethoxy]-3- isothiazol-4-yl- pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile

530.3 50-70% 272 4-[4-[3- Cyclopropyl-4- [(1R)-1-(5-fluoro- 2-pyridyl)ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]piperidine-1- carbonitrile

486.8 0-100% 273 7-[1-(1-Cyano-4- piperidyl)-3-(2- hydroxyethyl)-5- methyl-pyrazol-4- yl]-5-[(1R)-1-(5- fluoro-2-pyridyl) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

515.4 40-50% 274¹⁶ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-[4- (2,2,2- trifluoroethyl)- 1,2,4-triazol-3- yl]ethoxy]imidazo [1,2-a]pyridine-3- carbonitrile

526.1 275⁹ 7-[1-[2-(4- Cyanopiperazin-1- yl)-2-methyl- propyl]-5-methyl- triazol-4-yl]-5- [(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

511.4 276¹⁷ (3R,4S)-4-[4-[3- chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-fluoro- piperidine-1- carbonitrile, Isomer 2

515.2 50-60% 277 (3S,4S)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-fluoro- piperidine-1- carbonitrile, Isomer 2

515.1 40-60% 278 (3S,4R)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-triazol-1- yl]-3-fluoro- piperidine-1- carbonitrile, Isomer 2

515.2 40-50% 279 (3R,4R)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy- ethoxy]pyrazolo [1,5-a]pyridin-6-yl]- 5-methyl-triazol-1- yl]-3-fluoro- piperidine-1- carbonitrile, Isomer 2

515.20 40-60% 280^(18,19) 7-((1s,3s)-3-(4-(3- Chloro-4-((S)-1-(5- fluoropyridin-2-yl)- 2-hydroxyethoxy) pyrazolo[1,5- a]pyridin-6-yl)-5- methyl-1H-1,2,3- triazol-1-yl) cyclobutyl)-3-oxa- 7,9-diazabicyclo [3.3.1]nonane-9- carbonitrile, Isomer 2

594.4 10-95% 281^(20,21) 7-[1-[(2SR,4RS)-1- cyano-2- cyclopropyl-4- piperidyl]-5- methyl-triazol-4- yl]-5-[(1R)-1-(2- pyridyl)ethoxy] imidazo[1,2-a] pyridine-3- carbonitrile, Isomer 1

494.4 30-52% 282²³ (3S,4S)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy-ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-hydroxy- piperidine-1- carbonitrile, Isomer 2

513.1 30-45% 283²² (3R,4S)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy-ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-hydroxy- piperidine-1- carbonitrile, Isomer 2

513.2 284²² (3S,4R)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy-ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-hydroxy- piperidine-1- carbonitrile, Isomer 2

513.1 285⁹ (3R,4R)-4-[4-[3- Chloro-4-[1-(5- fluoro-2-pyridyl)-2- hydroxy-ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-3-hydroxy- piperidine-1- carbonitrile, Isomer 2

513.2 286 4-[4-[3-Fluoro-4- [1-(5-fluoro-2- pyridyl)-2- hydroxy-ethoxy] pyrazolo[1,5- a]pyridin-6-yl]-5- methyl-triazol-1- yl]-4-methyl- piperidine-1- carbonitrile, Isomer 2

495.2 40-50% ¹XBridge30 Prep C18 OBD Column, 19*150 mm, 5 μm, mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: ACN. ²Reverse flash chromatography: Column C18 silica gel, mobile phase A: H₂O (0.1% NH₃•H₂O), mobile phase B: ACN. ³XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm, mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: ACN. ⁴Prep-TLC (PE:EtOAc 1:2) ⁵Prep-TLC (DCM:MeOH 20:1). ⁶Reverse flash chromatography: column C18 silica gel, mobile phase A: H₂O (0.1% NH₄HCO₃), mobile phase B: ACN. ⁷XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm, mobile phase A: H₂O (10 mmol/L NH₄HCO₃), mobile phase B: MeOH. ⁸Reverse Flash Chromatography: Column C18 silica gel, mobile phase A: H₂O (0.1% FA), mobile phase B: ACN. ⁹Prep-TLC (EtOAc:PE 1:1). ¹⁰Prep-TLC (EtOAc:PE 10:1). ¹¹Reverse flash chromatography: Column C18 silica gel, mobile phase A: H₂O, mobile phase B: ACN. ¹²Reverse Flash Chromatography: Column C18 silica gel, mobile phase A: H₂O (0.1% NH₄HCO₃), mobile phase B: ACN. ¹³Reverse Flash Chromatography: Column C18 silica gel, mobile phase A: H₂O (0.1% FA), mobile phase B: ACN. ¹⁴Purification by trituration with iPrOH (5 mL). ¹⁵XBridge Shield RP18 OBD Column, 19*150 mm, 5 μm, mobile phase A: H₂O (0.05% NH₄OH), mobile phase B: ACN. ¹⁶Prep-TLC (DCM:MeOH 10:1). ¹⁷Reverse flash chromatography: Column C18 silica, gel eluting with a gradient of 50% to 60% ACN in H₂O. ¹⁸Reverse chromatography, Column C18 silica gel, eluting with ACN in H₂O (0.1% FA). ¹⁹After reverse phase purification fractions containing crude material are combined, pH adjusted to ~9.0 using sat. NaHCO₃. Material extracted with 3:1 CHCL₃:IPA. Organic phase is washed with H₂O, brine, dried over Na2_(S)O₄, filtered, and concentrated to a brown residue. Residue purified by reverse phase chromatography, eluting with 0% to 100% MeOH in DCM. ²⁰Purified by reverse chromatography; Column: XSelect CSH Prep C18 OBD, eluting with ACN in H₂O (0.1% FA). ²¹¹H NMR (400 MHz, DMSO-d6) δ 8.59 (dt, 1H), 8.48 (s, 1H), 7.86 (td, 1H), 7.64 (d, 1H), 7.57 (s, 1H), 7.37 (ddd, 1H), 6.82 (d, 1H), 6.02 (q, 1H), 4.67-4.43 (m, 1H), 3.66-3.51 (m, 1H), 3.29-3.11 (m, 1H), 2.47-2.36 (m, 4H), 2.22-1.91 (m, 4H), 1.80 (d, 3H), 1.05-0.86 (m, 1H), 0.70-0.61 (m, 1H), 0.59-0.51 (m, 1H), 0.49-0.42 (m, 1H), 0.35-0.22 (m, 1H). ²²Purified by Prep-TLC (EA). ²³Reverse chromatography, Column C18 silica gel, eluting with 30% to 45% ACN in H₂O (0.1% FA).

Example 287 (4R)-4-(4-[3-Cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azepane-1-carbonitrile

BrCN (22.22 mg, 0.21 mmol) in DCM (1 mL) is added dropwise to a stirred solution of 6-[1-[(4R)-azepan-4-yl]-5-methylpyrazol-4-yl]-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (70 mg, 0.20 mmol) and DIEA (260 mg, 2.0 mmol) in DCM (6 mL). The mixture is stirred for 3 hrs at RT under N₂ and then diluted with DCM (50 mL). The organic layers are washed with sat. NaHCO₃ (aq.) (2×40 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by reverse Combi-flash chromatography with the following conditions: Column, C18; eluting with a gradient of 0% to 100% ACN in H₂O (0.1% NH₄HCO₃) to give the title compound as an off-white solid (25.6 mg, 38%). ES/MS m/z 376.2 [M+H]⁺.

The following compounds are prepared essentially as described for (4R)-4-(4-[3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)azepane-1-carbonitrile using the appropriate reagents, adjusting the reaction time to determine completion of the reaction, and adjusting the purification system as appropriate.

TABLE 69 ES/MS Ex. m/z No. Chemical name Structure [M + H]⁺ 288¹ (4S)-4-(4-[3- Cyano-4- methoxypyrazolo [1,5-a]pyridin-6-yl]- 5- methylpyrazol-1- yl)azepane-1- carbonitrile

376.1 289^(2,3,11) 6-[5-(4- cyanopiperazin-1- yl)-4-methyl-1,2,4- triazol-3-yl]-4- methoxy-pyrazolo [1,5-a]pyridine-3- carbonitrile

363.1 290⁴ 7-[1-(1-cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(3- pyridyl)ethoxy] imidazo[1,2-a] pyridine-3- carbonitrile

454.1 291⁵ 6-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-4-[(1R)-1-(2- methylthiazol-4- yl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

474.1 292⁵ 6-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-4-[(1R)-1-(1- methylpyrazol-3- yl)ethoxy]pyrazolo [1,5-a]pyridine-3- carbonitrile

457.1 293⁶ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(2,4- difluorophenyl) ethoxy]imidazo[1,2- a]pyridine-3- carbonitrile

487.2 294⁷ 7-[1-(1-Cyano-4- piperidyl)-5- methyl-triazol-4- yl]-5-[(1R)-1-(4- fluorophenyl)ethoxy] imidazo[1,2- a]pyridine-3- carbonitrile

471.2 295^(8,10,9) 7-[1-(1-Cyano-4- piperidyl)-5- methyl-pyrazol-4- yl]-5-[(1R)-1-(5- fluoro-2- pyridyl)ethoxy] imidazo[1,2- c]pyrimidine-3- carbonitrile

472.2 296^(8,9,3) 4-[4-[3-Chloro-5- [(1R)-1-(5-fluoro- 2- pyridyl)ethoxy] imidazo[1,2- c]pyrimidin-7-yl]- 5-methyl-pyrazol- 1-yl]piperidine-1- carbonitrile

481.2 ¹Prep-TLC (PE:EtOAc 1:1), aqueous phase is quenched with NaClO solution at RT. ²Purified by reverse phase chromatography eluting with 10% to 95% ACN in H₂O (0.1% FA). ³Purified by reverse phase chromatography eluting with 0% to 10% MeOH in DCM. ⁴Purified by reverse flash phase chromatography eluting with 10% to 50% ACN in H₂O. ⁵Purified by reverse phase chromatography eluting with 0% to 100% ACN in H₂O (0.1% FA). ⁶Purified by reverse phase chromatography eluting with ACN in H₂O (0.1% FA). ⁷Purified by reverse phase chromatography eluting with 60% to 70% ACN in H₂O (0.1% NH₄HCO₃). ⁸Reaction is diluted with diluted with 3:1 CHCl₃:IPA, washed with water, brine, dried over Na₂SO₄, filtered and concentrated in vacuo. ⁹Purified by reverse phase chromatography eluting with 10% to 95% ACN in H₂O (0.1% FA). Fractions containing title compound are combined and pH adjusted to ~9.0 with aq. NaHCO₃. Mixture extracted with 3:1 CHCl₃:IPA. Organic phase washed with water, brine, dried over Na2_(S)O₄, filtered and concentrated in vacuo. ¹⁰Purified by reverse phase chromatography eluting with 10% to 100% ACN in H2O.

Example 297 4-[4-[3-Chloro-4-[(1R)-1-(2-cyanophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-pyrazol-1-yl]piperidine-1-carbonitrile

A solution of 4-(4-[4-[(1R)-1-(2-cyanophenyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methylpyrazol-1-yl)piperidine-1-carbonitrile (73 mg, 0.162 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (16 mg, 0.081 mmol) in DCM (5 mL) is stirred for 1 hr at RT under N₂. The reaction is quenched with sat. aq. NaHCO₃. The mixture is extracted with DCM (100 mL). The combined organic layers are washed with brine (10 mL) then concentrated in vacuo. The residue is purified by reverse flash chromatography: Column, C18; mobile phase, eluting with 10% to 70% ACN in H₂O (0.1% NH₄HCO₃), 254 nm to afford the title compound (60 mg, 76.37%) as a white solid (60 mg, 76%). ES/MS m/z 486.0 [M+H]⁺.

Example 298 4-[4-[3-Chloro-4-[2-(2,2-difluoroethylamino)-1-(5-fluoro-2-pyridyl)ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]piperidine-1-carbonitrile, Isomer 2

To a solution of 4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy) pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carbonitrile (150 mg, 0.302 mmol) and DIPEA (117 mg, 0.906 mmol) in DCM (1.5 mL) at −78 C is added Tf₂O (111 mg, 0.392 mmol). The cooling bath is then switched to a brine/ice bath and the reaction is stirred 1 hr at −20° C. Next, a solution of 2,2-difluoroethan-1-amine (24.5 mg, 0.302 mmol) in DCM (0.5 mL) is slowly added to the reaction and the cooling bath is allowed to expire overnight. The reaction mixture is diluted with DCM (10 mL) and washed with NaHCO₃ (10 mL), brine (10 mL), and the layers are separated. The organic layer is concentrated in vacuo. The residue is purified by reverse phase chromatography eluting with a gradient of 0% to 100% ACN in H₂O to afford the title compound (110 mg, 65%). ES/MS m/z 560.4 [M+H]⁺.

The following compounds can be prepared essentially as described in the methods above.

TABLE 70 Ex. No. Chemical name Structure 299 (3S,4S)-4-[4-[3-Chloro-4- [(1S)-1-(5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- pyrazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

300 (3S,4S)-4-[4-[3-Chloro-4- [(1R)-1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

301 (3S,4S)-4-[4-[3-Chloro-4- [(1S)-2,2,2-trifluoro-1-(5- fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

302 (3S,4S)-4-[4-[3-Chloro-4- [(1S)-2-fluoro-1-(5-fluoro-2- pyridyl)ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

303 (3S,4S)-4-[4-[3-Chloro-4-[2- (5-fluoro-2-pyridyl)-2- hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

304 (3S,4S)-4-[4-[3Chloro-4-[2- (5-fluoro-2-pyridyl)-2- hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-hydroxy- piperidine-1-carbonitrile

305 (3R,4R)-4-[4-[3-Fluoro-4- [(1S)-1-(5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-methyl- piperidine-1-carbonitrile

306 (3R,4S)-4-[4-[3-Fluoro-4- [(1S)-1-(5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-methyl- piperidine-1-carbonitrile

307 (3S,4S)-4-[4-[3-Fluoro-4- [(1S)-1-(5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-methyl- piperidine-1-carbonitrile

308 (3S,4R)-4-[4-[3-Fluoro-4- [(1S)-1-(5-fluoro-2-pyridyl)- 2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]-3-methyl- piperidine-1-carbonitrile

309 (3R,4S)-3-Fluoro-4-[4-[3- fluoro-4-[(2S)-2-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

310 (3R,4S)-3-Fluoro-4-[4-[3- fluoro-4-[(2R)-2-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

311 (3R,4S)-3-Fluoro-4-[4-[3- fluoro-4-[2-(5-fluoro-2- pyridyl)-2-hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

312 (3R,4S)-3-fluoro-4-[4-[3- fluoro-4-[2-(5-fluoro-2- pyridyl)-2-hydroxy- propoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

313 (3R,4R)-3-fluoro-4-[4-[3- fluoro-4-[(1S)-1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

314 (3R,4S)-3-fluoro-4-[4-[3- fluoro-4-[(1S)-1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

315 (3S,4S)-3-fluoro-4-[4-[3- fluoro-4-[(1S)-1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

316 (3S,4R)-3-fluoro-4-[4-[3- fluoro-4-[(1S)-1-(5-fluoro-2- pyridyl)-2-hydroxy- ethoxy]pyrazolo[1,5- a]pyridin-6-yl]-5-methyl- triazol-1-yl]piperidine-1- carbonitrile

Biological Assays

The following assays demonstrate that compounds provided herein are FGFR3 inhibitors The following assays demonstrate that certain compounds provided herein selectively target FGFR3.

FGFR3 and FGFR1 Enzyme Assay

FGFR3 protein was purchased from Reaction Biology (Cat. No. 1068), and FGFR1 protein was purchased from ThermoFisher Scientific (Cat. No. PV4105). Enzyme activity was monitored using the KinEASE™-TK Assay Kit (Cisflio, Cat. No. 62TK0PEC) according to the manufacturer's instructions. All assays were performed at the respective KmATP for each kinase in KinEASE™ Kinase Buffer. Reactions were performed in a white, small volume polystyrene 384 well plate (Greiner, Cat. No. 784075-25).

An incubation was conducted with FGFR3 protein or FGFR1 protein, 125.0 nM TK-Biotin Substrate (CisBio), 7.81 nM Streptavidin-XL665 (CisBio), 0.25× Anti-Phosphorylate TK-Biotin-Cryptate (CisBio). Final enzyme concentrations were 0.25 nM in 10 uL reactions. Titration of compounds were performed in a half-log manner in 100% dimethyl sulfoxide (DMSO) starting at 1 uM. Prior to the initiation of the reaction by adenosine triphosphate (ATP), FGFR1 protein and compounds were pre-incubated for 15 minutes at room temperature, and FGFR3 protein and compounds were pre-incubated on ice for 15 minutes. Reactions proceeded for 30 min at 30° C. Plates were quenched by the addition of the Anti-TK cryptate antibody/Streptavidin-XL665 mixture. After 1 hour. in the stopping solution, the plates were read on the Envision plate reader ((Perkin Elmer) (Ex. Filter. 320 nm and Em1 665 nm/Em2 615 nm)).

Ratios were converted to a percent of control (POC) using a ratiometric emission factor. One hundred POC was determined using no test compound, and 0 POC was determined in the presence of 1 uM of an appropriate control inhibitor. A 4-parameter logistic curve was fit to the POC values as a function of the concentration of compound, and the IC₅₀ value was the point where the best fit curve crossed 50 POC.

In the above assays the compounds of Examples 1-160, 165-275, 280, 281 and 287-298 all exhibited IC₅₀ values of less than 350 nM for FGFR3.

In the above assays the compounds of Examples 13, 21, 22, 24, 26, 41, 43, 45, 47, 48, 49, 51, 53, 61, 63, 68, 75, 77, 79, 94, 99, 142, 152, 154, 155, 156, 157, 169, 170, 171, 173, 179, 183, 189, 195, 201, 208, 209, 212, 215, 222, 225, 226, 228, 233, 245, 257, 264, 274, 280, 281, 291, 292 and 297 all exhibited IC₅₀ values of less than 100 nM for FGFR3 and are at least 3 fold more selective for FGFR3 than for FGFR1.

In the above assays the compounds of Examples 21, 22, 24, 26, 41, 43, 45, 47, 48, 49, 51, 53, 61, 63, 68, 79, 94, 99, 152, 154, 155, 156, 157, 169, 170, 171, 173, 179, 183, 189, 195, 201, 208, 209, 212, 215, 222, 226, 228, 245, 257, 280, 281, 291, 292 and 297 all exhibited IC₅₀ values of less than 50 nM for FGFR3 and are at least 10 fold more selective for FGFR3 than for FGFR1. 

The invention claimed is:
 1. A compound of the formula:

wherein A is pyrazole, triazole, thiadiazole or oxadiazole, substituted with R¹ and R^(1A); R¹ is hydrogen or C₁-C₃ alkyl; R^(1A) is hydrogen, halo, CN, or C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH₃; X₁ and X₂ are independently selected from N and C, wherein when one of X₁ or X₂ is N the other is C; X₃ is N or CH; X₄ is N or C—R⁹; Y is NH, O, S or a bond; Y₁ is a bond, CHR⁷, CH₂—CHR⁷, CHR⁷—CH₂, CF₂, CH₂—CF₂ or CF₂—CH₂; Y₂ is a bond, CHR³, CH₂—CHR³, CHR³—CH₂, CF₂, CH₂—CF₂ or CF₂—CH₂; Y₃ is CR⁴R⁵ or CF₂; Y₄ is CR³R⁴, or CF₂; Z is a bond, CHR^(9A), CR⁴R^(4A), CR⁴R^(4A)—CH₂, CH₂—CR⁴R^(4A), cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine; Z₁ is a bond when Z is a bond, CR⁴R^(4A), CR⁴R^(4A)—CH₂, CH₂—CR⁴R^(4A), cyclobutyl, cyclopentyl, cyclohexyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine, pyrrolidine or piperidine, or Z₁ is CH₂ or CH₂—CH₂ when Z is CHR^(9A); Z₂ is a bond, C(O), SO₂ or —NR₄C(O); Z₃ is a bond, C(O), SO₂ or —NR₄C(O); R² is C₁-C₅ alkyl or R⁸, wherein C₁-C₅ alkyl is optionally substituted with one or more substituents independently selected from halo, OH, CN, oxo, —OC₁—C₄ alkyl, —OC₃—C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alky and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; R³ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl, cyclopropyl, or one R³ is fused with R⁵ or R⁷ to form CH₂, CH₂—CH₂ or CH₂OCH₂; R⁴ is hydrogen or C₁-C₃ alkyl; R^(4A) is hydrogen, halo, OH, or C₁-C₃ alkyl; R⁵ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl, cyclopropyl, or is fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂; R⁶ is hydrogen, halo, C₁-C₅ alkyl, CN, 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, wherein 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, methyl, halomethyl, OH or OCH₃ and wherein C₁-C₅ alkyl is optionally substituted with one or more substituents independently selected from halo, OH and OCH₃; R⁷ is hydrogen, F, OH, OCH₃, C₁-C₃ alkyl or is fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂; R⁸ is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A); R^(8A) is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl; R⁹ is hydrogen, C₁-C₃ alkyl, or is fused with R^(9A) to form CH₂ or CH₂—CH₂; R¹⁰ is 3-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl, optionally fused or substituted with R^(8A); R¹¹ is C₁-C₄ alkyl, NH₂, NHC₁—C₃ alkyl, NHC₃-C₅ cycloalkyl or N(C₁-C₃ alkyl)₂, wherein C₁-C₄ alkyl, C₁-C₃ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; R¹² is C₁-C₄ alkyl, C₃-C₅ cycloalkyl, NH₂, NHC₁—C₃ alkyl, NHC₃-C₅ cycloalkyl or N(C₁-C₃ alkyl)₂, wherein C₁-C₄ alky, C₁-C₃ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; and R⁸, R¹⁰ and R^(8A) are optionally substituted with one or more substituents independently selected from halo, OH, CN, —OC₁—C₄ alkyl, —OC₃—C₅ cycloalkyl and —Z₃—R¹² wherein C₁-C₄ alky and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN; or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1 wherein X₁ is C, and X₂ is N; or X₁ is N, and X₂ is C.
 3. The compound according to claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.
 4. The compound according to claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.
 5. The compound according to claim 1, wherein X₃ is CH, or a pharmaceutically acceptable salt thereof.
 6. The compound according to claim 1, wherein R¹ is methyl, or a pharmaceutically acceptable salt thereof.
 7. The compound according to claim 1, wherein R^(1A) is hydrogen or C₁-C₃ alkyl optionally substituted with one or more substituents independently selected from halo, OH, and OCH₃, or a pharmaceutically acceptable salt thereof.
 8. The compound according to claim 1, wherein R^(1A) is hydrogen, or a pharmaceutically acceptable salt thereof.
 9. The compound according to claim 1, wherein R⁹ is hydrogen or is fused with R^(9A) to form CH₂ or CH₂—CH₂, or a pharmaceutically acceptable salt thereof.
 10. The compound according to claim 1, wherein R⁶ is CN, F, CI, CH₃, CF₃ or cyclopropyl, or a pharmaceutically acceptable salt thereof.
 11. The compound according to claim 1, wherein R⁶ is CN, F or C, or a pharmaceutically acceptable salt thereof.
 12. The compound according to claim 1, wherein R⁶ is CN or C, or a pharmaceutically acceptable salt thereof.
 13. The compound according to claim 1 wherein A is pyrazole or triazole, substituted with R¹ and R^(1A), or a pharmaceutically acceptable salt thereof.
 14. The compound according to claim 1, wherein Z is a bond, cyclobutyl, bicyclo(1.1.1)pentane, bicyclo(2.1.1)hexane, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.
 15. The compound according to claim 1, wherein Z is a bond, cyclobutyl, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.
 16. The compound according to claim 1, wherein R² is C₁-C₃ alkyl optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁—C₄ alkyl, —OC₃—C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, or a pharmaceutically acceptable salt thereof.
 17. The compound according to claim 1, wherein R² is selected from:

optionally substituted with one, two, three or four substituents independently selected from halo, OH, CN, oxo, —OC₁—C₄ alkyl, —OC₃—C₅ cycloalkyl, —Z₂—R¹¹ and R¹⁰, wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one or more substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, wherein * indicates the connection point to Y, or a pharmaceutically acceptable salt thereof.
 18. The compound according to claim 17, wherein R² is optionally substituted with one, two, three or four substituents independently selected from F, OH, CN, oxo, —OCH₃ and —OC₃ cycloalkyl, or a pharmaceutically acceptable salt thereof.
 19. The compound according to claim 1, wherein R¹⁰ is 4-6 membered heterocycloalkyl or 5-6 membered heteroaryl, optionally fused with R^(8A), or a pharmaceutically acceptable salt thereof.
 20. The compound according to claim 1, wherein R¹⁰ is 5-6 membered heteroaryl, optionally fused with R^(8A), or a pharmaceutically acceptable salt thereof.
 21. The compound according to claim 19, wherein R¹⁰ and R^(8A) are optionally substituted with one, two or three substituents independently selected from halo, OH, CN, —OC₁—C₄ alkyl, —OC₃—C₅ cycloalkyl and —Z₃—R¹² wherein C₁-C₄ alkyl and C₃-C₅ cycloalkyl are optionally substituted with one, two or three substituents independently selected from halo, OH, OCH₃, methylamine, N,N-dimethylamine and CN, or a pharmaceutically acceptable salt thereof.
 22. The compound according to claim 1, wherein Y₁ is a bond, CHR⁷, CH₂—CHR⁷ or CHR⁷—CH₂, wherein R⁷ is selected from hydrogen, F, OH and CH₃, or a pharmaceutically acceptable salt thereof.
 23. The compound according to claim 1, wherein Y₂ is a bond, CHR³, CH₂—CHR³ or CHR³—CH₂, wherein R³ is selected from hydrogen, F, OH and CH₃, or a pharmaceutically acceptable salt thereof.
 24. The compound according to claim 1, wherein Y₃ is CR⁴R⁵ or CF₂ wherein R⁴ is hydrogen or CH₃ and R⁵ is hydrogen, F, OH or CH₃, or a pharmaceutically acceptable salt thereof.
 25. The compound according to claim 1, wherein Y₃ is CR⁴R⁵ wherein R⁴ is hydrogen and R⁵ is fused with one R³ to form CH₂, CH₂—CH₂ or CH₂OCH₂, or a pharmaceutically acceptable salt thereof.
 26. The compound according to claim 1, wherein Y₄ is CR³R⁴ or CF₂ wherein R⁴ is hydrogen or CH₃ and R³ is hydrogen, F, OH or CH₃, or a pharmaceutically acceptable salt thereof.
 27. The compound according to claim 1, wherein Y is NH or O, or a pharmaceutically acceptable salt thereof.
 28. The compound according to claim 27, wherein Y is O, or a pharmaceutically acceptable salt thereof.
 29. The compound according to claim 1, wherein Z is a bond, azetidine or piperidine, or a pharmaceutically acceptable salt thereof.
 30. The compound according to claim 1, wherein Z₁ is a bond, or a pharmaceutically acceptable salt thereof.
 31. The compound according to claim 1, wherein Z is CHR^(9A), Z₁ is CH₂ and R⁹ is fused with R^(9A) to form CH₂, or a pharmaceutically acceptable salt thereof.
 32. The compound according to claim 1, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 33. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutically acceptable carrier, diluent or excipient.
 34. A method of treating cancer, comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract cancer, urothelial upper tract cancer, urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma, cutaneous melanoma, head and neck cancer, oral cancer, thyroid cancer, renal cancer, renal pelvis cancer, glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer.
 35. The method of claim 34 wherein the treatment is cancer and the cancer is selected from the group consisting of breast cancer, invasive ductal breast cancer, invasive lobular breast cancer, lung cancer, non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer, small-cell lung cancer, urothelial cancer, bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer, muscle invasive bladder cancer upper tract cancer, urothelial upper tract cancer, and glioblastoma.
 36. The method of claim 35, wherein the cancer is selected from the group consisting of bladder cancer, urothelial bladder cancer, non-muscle invasive bladder cancer and muscle invasive bladder cancer.
 37. The method of claim 34, wherein the cancer is FGFR3-associated cancer. 